Biaromatic ligand activators of PPARgamma receptors

ABSTRACT

Novel pharmaceutical/cosmetic compositions contain at least one biaromatic ligand activator of a PPARγ receptor, such biaromatic ligand having the structural formula (I):  
                 
 
     and are well suited, inter alia, for regulating and/or restoring skin lipid metabolism, for treating a wide variety of dermatological afflictions, and for preventing and/or treating the signs of aging and/or dry skin.

CROSS-REFERENCE TO PRIORITY/PROVISIONAL APPLICATIONS

[0001] This application claims priority under 35 U.S.C. §119 ofFR-01/16750, filed Dec. 21, 2001, of FR-02/02647, filed Mar. 1, 2002,and of provisional application Serial No. 60/351,425, filed Jan. 28,2002, each hereby expressly incorporated by reference. This applicationis also a continuation of said '425 provisional.

BACKGROUND OF THE INVENTION

[0002] 1. Technical Field of the Invention

[0003] The invention relates, as novel and useful industrial products,to biaromatic compounds which are activators of receptors of thePeroxisome Proliferator-Activated Receptor type of subtype γ (PPARγ). Italso relates to their method of preparation and to their use inpharmaceutical compositions for use in human or veterinary medicine, oralternatively in cosmetic compositions.

[0004] 2. Description of the Prior Art

[0005] The activity of the PPAR-type receptors has been the subject ofnumerous studies. There may be mentioned, as a guide, the publicationentitled “Differential Expression of Peroxisome Proliferator-ActivatedReceptor Subtypes During the Differentiation of Human Keratinocytes”,Michel Rivier et al., J. Invest. Dermatol 111, 1998, p. 1116-1121, inwhich a large number of bibliographic references relating to PPAR-typereceptors is listed. There may also be mentioned, as a guide, thedossier entitled “The PPARs: From orphan receptors to Drug Discovery”,Timothy M. Willson, Peter J. Brown, Daniel D. Sternbach, and Brad R.Henke, J. Med. Chem., 2000, Vol. 43, p. 527-550.

[0006] The PPAR receptors activate transcription by binding to elementsof DNA sequences, called peroxisome proliferator response elements(PPRE), in the form of a heterodimer with the retinoid X receptors(called RXRs).

[0007] Three human PPAR subtypes have been identified and described:PPARα, PPARγ and PPARδ (or NUC1).

[0008] PPARα is mainly expressed in the liver while PPARδ is ubiquitous.

[0009] PPARγ is the most widely studied of the three subtypes. All thereferences suggest a critical role of the PPARγ receptors in theregulation of differentiation of adipocytes, where it is highlyexpressed. It also plays a key role in systemic lipid homeostasis.

[0010] It has in particular been described in Patent Application WO96/33724 that PPARγ-selective compounds, such as prostaglandin-J2 or-D2, are potential active agents for treating obesity and diabetes.

[0011] Moreover, the applicant has already described in PatentApplication FR98/02894 the use of PPARγ-activating compounds in thepreparation of a pharmaceutical composition, the composition beingintended for treating skin disorders linked to an abnormality ofdifferentiation of epidermal cells.

SUMMARY OF THE INVENTION

[0012] One of the aims of the present invention is to provide novelPPARγ-activating compounds exhibiting a better biological activity thanthe prior art compounds.

[0013] Thus, the present invention relates to biaromatic compoundscorresponding to the following general formula:

[0014] in which:

[0015] R₁ represents a radical of the following formulae (a) or (b):

[0016] R₅ and R₆ having the meanings given below,

[0017] R₂ and R₃, which may be identical or different, represent ahydrogen atom, an alkyl radical having from 1 to 6 carbon atoms, an arylradical, a halogen atom, a radical —OR₇, a polyether radical, a nitroradical or an amino radical which may be optionally substituted withalkyl radicals having from 1 to 6 carbon atoms;

[0018] R₇ having the meaning given below,

[0019] X represents the bonds having the following structures:

[0020] —CH₂—N(R₈)—CO—

[0021] —N(R₈)—CO—N(R₉)—

[0022] —N(R₈)—CO—CH₂—

[0023] —N(R₈)—CH₂—CO—

[0024]  which may be read from left to right or conversely

[0025] R₈ and R₉ having the meanings given below,

[0026] —R₄ represents:

[0027] a phenyl, benzyl, phenethyl, thienyl, furyl or pyridyl radical,all these radicals being substituted with a group R₁₀,

[0028] R₁₀ having the meanings given below,

[0029] a pyrrolyl, pyrazinyl, naphthyl, biphenyl, indolyl, indenyl,benzothienyl, benzofuryl, benzothiazolyl or quinolyl radical, it beingpossible for all these radicals to be mono- or disubstituted with agroup R₁, and/or R₁₂,

[0030] R₁₁ and R₁₂ having the meanings given below,

[0031] a radical —(CH₂)n—(CO)_(q)R₁₃,

[0032] n, q and R₁₃ having the meanings given below,

[0033] an adamantyl, diphenylmethyl, diphenylethyl, diphenylpropyl,diphenylbutyl, cyclopropylmethyl, cyclopentylethyl,2-benzimidazolyl-ethyl, cyclohexylmethyl, phenoxyphenyl, 9H-fluorenyl,benzyloxyphenyl, 4-heptyloxyphenyl, or4-(6-methyl-2-benzothiazolyl)phenyl radical,

[0034] a radical —(CH₂)n—O—R₁₃,

[0035] n and R₁₃ having the meanings given below,

[0036] R₅ represents a hydroxyl radical or an alkoxy radical having from1 to 9 carbon atoms,

[0037] R₆ represents an alkyl radical having from 1 to 6 carbon atoms, aradical OR₁₄ or a radical SR₁₄,

[0038] R₁₄ having the meanings given below,

[0039] R₇ represents a hydrogen atom, an alkyl radical having from 1 to6 carbon atoms, an aryl radical or an aralkyl radical,

[0040] R₈ represents a hydrogen atom or an alkyl radical having from 1to 6 carbon atoms,

[0041] R₉ represents a hydrogen atom or an alkyl radical having from 1to 6 carbon atoms,

[0042] R₁₀ represents:

[0043] a radical —S(O)_(m)R₁₅

[0044] a radical —(CH₂)p—COR₁₆

[0045] a radical —O—R₁₇

[0046] m, p, R₁₅, R₁₆ and R₁₇ having the meanings given below,

[0047] R₁₁ and R₁₂ represent a halogen atom, a radical CF₃, an alkylradical having from 1 to 12 carbon atoms, an alkoxy radical having from1 to 9 carbon atoms, a polyether radical, a nitro functional group, ahydroxyl radical optionally protected by an acetyl or benzoyl group, anamino functional group optionally substituted with at least one alkylhaving from 1 to 12 carbon atoms or with a radical —CONH—R₂₄, orprotected by an acetyl or benzoyl group, a radical —S(O)_(m)R₁₅, aradical (CH₂)p—COR₁₆ or a radical —OR₁₇,

[0048] m, p, R₁₅, R₁₆, R₁₇ and R₂₄ having the meanings given below,

[0049] n may take the values ranging from 1 to 9,

[0050] q may take the values 0 or 1,

[0051] R₁₃ represents a radical —OR₁₈, a radical

[0052] N(R₁₉)(R₂₀), an aryl radical, an aralkyl radical or a heteroarylradical,

[0053] R₁₈, R₁₉ and R₂₀ having the meanings given below,

[0054] m may take the values 0, 1 or 2,

[0055] p may take the values 0, 1 or 2,

[0056] R₁₄ represents an alkyl radical having from 1 to 12 carbon atoms,a radical CF₃, an aryl radical or an aralkyl radical,

[0057] R₁₅ represents an alkyl radical having from 1 to 12 carbon atoms,an aryl radical or an aralkyl radical,

[0058] R₁₆ represents an alkyl radical having from 1 to 12 carbon atoms,a radical

[0059] OR₂₁, a radical —N(R₂₂)(R₂₃), an aryl radical or an aralkylradical,

[0060] R₂₁, R₂₂ and R₂₃ having the meanings given below,

[0061] R₁₇ represents an aryl radical or an aralkyl radical,

[0062] R₁₈ represents a hydrogen atom or an alkyl radical having from 1to 12 carbon atoms,

[0063] R₁₉ and R₂₀, which may be identical or different, represent ahydrogen atom, an alkyl radical having from 1 to 12 carbon atoms, ortaken together may form a heterocycle,

[0064] R₂₁, represents a hydrogen atom or an alkyl radical having from 1to 12 carbon atoms,

[0065] R₂₂ and R₂₃, which may be identical or different, represent ahydrogen atom, an alkyl radical having from 1 to 12 carbon atoms, ortaken together may form a heterocycle,

[0066] R₂₄ represents a phenyl, diphenylmethyl, diphenylpropyl,diphenylbutyl, biphenylyl, phenoxyphenyl, 9H-fluorenyl,4-benzyloxyphenyl, 4-heptyloxyphenyl, or4-(6-methyl-2-benzothiazolyl)phenyl radical, and the salts of thecompounds of formula (I) when R₁ contains a carboxylic acid functionalgroup and the optical and geometric isomers of the said compounds offormula (I).

[0067] The present invention also relates to the salts of the compoundsof formula (I) when R₁ contains a carboxylic acid functional group andthe optical and geometric isomers of the said compounds of formula (I).

DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS OFTHE INVENTION

[0068] When the compounds according to the invention are provided in theform of a salt, this is preferably a salt of an alkali or alkaline-earthmetal, or alternatively a zinc salt or salts of an organic amine.

[0069] According to the present invention:

[0070] The expression alkyl radical having from 1 to 6 carbon atoms ispreferably understood to mean the methyl, ethyl, isopropyl, butyl,tert-butyl and hexyl radicals.

[0071] The expression alkyl radical having from 1 to 12 carbon atoms ispreferably understood to mean the methyl, ethyl, isopropyl, butyl,tert-butyl, hexyl, octyl, decyl and dodecyl radicals.

[0072] The expression polyether radical is preferably understood to meana radical having from 1 to 6 carbon atoms interrupted by at least oneoxygen atom such as the methoxymethoxy, ethoxymethoxy andmethoxyethoxymethoxy radicals.

[0073] The expression halogen atom is preferably understood to mean afluorine, chlorine or bromine atom.

[0074] The expression alkoxy radical having from 1 to 9 carbon atoms ispreferably understood to mean the methoxy, ethoxy, isopropyloxy,tert-butoxy and hexyloxy radicals.

[0075] The expression aryl radical is preferably understood to mean aphenyl, biphenyl, cinnamyl or naphthyl radical which may be mono- ordisubstituted with a halogen atom, a radical CF₃, an alkyl radicalhaving from 1 to 12 carbon atoms, an alkoxy radical having from 1 to 7carbon atoms, a nitro functional group, a polyether radical, an arylradical, a benzoyl radical, an alkyl ester group, a carboxylic acid, ahydroxyl radical optionally protected by an acetyl or benzoyl group oran amino functional group optionally protected by an acetyl or benzoylgroup or optionally substituted with at least one alkyl having from 1 to12 carbon atoms.

[0076] The expression aralkyl radical is preferably understood to mean abenzyl or phenethyl radical which may be mono- or disubstituted with ahalogen atom, a radical CF₃, an alkyl radical having from 1 to 12 carbonatoms, an alkoxy radical having from 1 to 6 carbon atoms, a nitrofunctional group, a polyether radical, a hydroxyl radical optionallyprotected by an acetyl or benzoyl group or an amino functional groupoptionally protected by an acetyl or benzoyl group or optionallysubstituted with at least one alkyl having from 1 to 12 carbon atoms.

[0077] The expression heteroaryl radical is preferably understood tomean an aryl radical interrupted by one or more heteroatoms, such as thepyridyl, furyl, thienyl, isoxazolyl, oxadiazolyl, oxazolyl,benzimidazole, indolyl or benzofuran radical, optionally substitutedwith at least one halogen, an alkyl having from 1 to 12 carbon atoms, analkoxy having from 1 to 7 carbon atoms, an aryl radical, a nitrofunctional group, a polyether radical, an aryl radical, a benzoylradical, an alkyl ester group, a carboxylic acid, a hydroxyl optionallyprotected by an acetyl or benzoyl group or an amino functional groupoptionally protected by an acetyl or benzoyl group or optionallysubstituted with at least one alkyl having from 1 to 12 carbon atoms.

[0078] The expression heterocycle is preferably understood to mean themorpholino, piperidino, piperazino, 2-oxopiperidin-1-yl and2-oxopyrrolidin-1-yl radicals optionally substituted with at least onealkyl group having from 1 to 12 carbon atoms, an alkoxy having from 1 to7 carbon atoms, an aryl radical, a nitro functional group, a polyetherradical, an aryl radical, a benzoyl radical, an alkyl ester group, acarboxylic acid, a hydroxyl optionally protected by an acetyl or benzoylgroup or an amino functional group optionally protected by an acetyl orbenzoyl group or optionally substituted with at least one alkyl havingfrom to 1 to 12 carbon atoms.

[0079] Among the compounds corresponding to the above general formula(I), the following may be mentioned, alone or as a mixture:

[0080] 1-methyl7-{[4′-(2,4-dioxothiazolidin-5-ylmethyl)-biphenyl-3-ylmethyl]methylcarbamoyl}heptanoate;

[0081] 2-methyl9-{[4′-(2,4-dioxothiazolidin-5-ylmethyl)-biphenyl-3-ylmethyl]methylcarbamoyl}nonanoate;

[0082] 3-methylN-[4′-(2,4-dioxothiazolidin-5-ylmethyl)-biphenyl-3-ylmethyl]-N-methylterephthalamate;

[0083]4-3-cyclopentyl-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylpropionamide;

[0084]5-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-1-carboxamide;

[0085]6-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;

[0086]7-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-2-phenoxyacetamide;

[0087]8-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-1-methyl-1H-pyrrole-2-carboxamide;

[0088]9-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyladamantane-1-carboxamide;

[0089]10-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbiphenyl-4-carboxamide;

[0090]11-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbenzo[b]thiophene-2-carboxamide;

[0091]12-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-6-oxo-6-phenylhexanamide;

[0092]13-4-dimethylamino-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-1-carboxamide;

[0093]14-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-4-methanesulphonyl-N-methylbenzamide;

[0094]15-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4-(1-phenylmethanoyl)benzamide;

[0095]16-6-(2-methoxyethoxymethoxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;

[0096]17-6-hydroxy-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)-biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;

[0097]18-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4-methylsulphanylbenzamide;

[0098]19-(S)-3-(3′-{[(1-biphenyl-4-ylmethanoyl)methyl-amino]methyl}biphenyl-4-yl)-2-ethoxypropionicacid;

[0099]20-(S)-2-ethoxy-3-(3′-{[methyl-(6-oxo-6-phenylhexanoyl)amino]methyl}biphenyl-4-yl)propionicacid;

[0100]21-1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-1-methyl-3-naphthalen-2-ylurea;

[0101]22-3-(4-dimethylaminophenyl)-1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-1-methylurea;

[0102]23-(S)-2-ethoxy-3-{3′-[({1-[6-(2-methoxyethoxy-methoxy)naphthalen-2-yl]methanoyl}methylamino)methyl]-biphenyl-4-yl}propionicacid;

[0103]24-6-(methoxymethoxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;

[0104]25-6-(methoxycarbonyl)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;

[0105]26-6-(propyloxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;

[0106]27-6-(hexyloxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;

[0107]28-6-(nonyloxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;

[0108]29-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4′-propylbiphenyl-2-carboxamide;

[0109]30-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4-phenoxybenzamide;

[0110]31-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-7-oxo-7-phenylheptanamide;

[0111]32-(6-{[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamoyl}naphthalen-2-yloxy)aceticacid;

[0112]33-(6-{[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamoyl}naphthalen-2-yloxy)aceticacid methyl ester;

[0113]34-6-methoxy-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;

[0114]35-6-acetoxy-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;

[0115]36-6-amino-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;

[0116]37-6-acetylamino-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;

[0117]38-1-hydroxy-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;

[0118]39-1-methoxy-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;

[0119]40-6-bromo-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;

[0120]41-6-carboxyl-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;

[0121]42-6-carboxyl-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamidemethyl ester;

[0122]43-6-(3-phenylureido)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;

[0123]44-3-hydroxy-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;

[0124]45-3-methoxy-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;

[0125]46-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4′-hydroxybiphenyl-4-carboxamide;

[0126]47-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4′-methoxybiphenyl-4-carboxamide;

[0127]48-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4′-propyloxybiphenyl-4-carboxamide;

[0128]49-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4′-hexyloxybiphenyl-4-carboxamide;

[0129]50-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4′-acetoxybiphenyl-4-carboxamide;

[0130]51-(4′-{[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamoyl}biphenyl-4-yloxy)aceticacid;

[0131]52-(4′-{[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamoyl}biphenyl-4-yloxy)aceticacid methyl ester;

[0132]53-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4′-methoxymethoxybiphenyl-4-carboxamide;

[0133]54-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4′-nonyloxybiphenyl-4-carboxamide;

[0134]55-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4′-(2-methoxyethoxy)biphenyl-4-carboxamide;

[0135]56-3-biphenyl-4-yl-1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-1-methylurea;

[0136]57-1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-3-(9H-fluoren-2-yl)-1-methylurea;

[0137]58-1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-3-(9H-fluoren-9-yl)-1-methylurea;

[0138]59-3-benzhydryl-1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-1-methylurea;

[0139]60-1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-1-methyl-3-(3-phenoxyphenyl)urea;

[0140]61-1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-3-(4-heptyloxyphenyl)-1-methylurea;

[0141]62-3-(4-benzyloxyphenyl)-1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-1-methylurea;

[0142]63-1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-1-methyl-3-[4-(6-methylbenzothiazol-2-yl)phenyl]urea;

[0143]64-4′-(2-methoxyethoxymethoxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbiphenyl-4-carboxamide;

[0144]65-4′-hydroxy-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbiphenyl-4-carboxamide;

[0145]66-1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-3-(4-hexyloxyphenyl)-1-methylurea.

[0146] According to the present invention, the more particularlypreferred compounds of formula (I) are those for which:

[0147] —R₁ represents the radical of formula (a) or the radical offormula (b) where R₅ represents a hydroxyl radical and R₆ represents theradical OR₁₄ and/or

[0148] X represents the linkage having the structure —CH₂—N(R₈)—CO— or—N(R₈)—CO—N(R₉)— read from left to right or conversely.

[0149] The subject of the present invention is also the methods forpreparing the compounds of formula (I), in particular according to thereaction schemes given in FIGS. 1 and 2.

[0150] In FIG. 1, the derivatives of formula (Ia) and (Ib) may beobtained respectively from the derivatives (2) and (4) by acylation ofthe amine functional group with an activated form of a carboxylic acid,for example an acid chloride (Cl—CO—R₄), in the presence of a tertiaryamine (for example triethylamine or pyridine) in an anhydrous solvent,preferably THF, it being possible for the derivatives (2) and (4) to beobtained respectively from the compounds (1) and (3) by deprotection ofthe amine functional group in the presence of trifluoroacetic anhydrideor hydrochloric acid in a solvent such as THF or dichloromethane.

[0151] The derivatives of formula (Ic) may be obtained (FIG. 1) from thederivatives (4) by reaction with an isocyanate of formula O═C═N—R₄ in asolvent such as dichloromethane in the presence of a base such astriethylamine.

[0152] The derivatives of formula (Id) may be obtained (FIG. 1) from thederivatives (4) by reaction with an alpha-bromoketone (Br—CH₂—CO—R₄) ina solvent such as acetone or methyl ethyl ketone in the presence of abase such as potassium carbonate.

[0153] The derivatives (1a) and (3a) may be obtained (FIG. 2) from thecompounds (10) either by hydrogenation in the presence of palladium oncarbon or Raney nickel in a solvent such as ethyl acetate, dioxane, DMFor ethyl alcohol or by reduction in the presence of lithium borohydrideand pyridine in THF. The compounds (10) may be obtained from thecompounds (8) by reaction with 2,4-thiazolidinedione (9) in the presenceof piperidine acetate in an alcoholic solvent such as ethanol or intoluene. The compounds (8) may be obtained from halogenated derivatives(6), preferably from iodinated or brominated derivatives, by a Suzukitype coupling reaction with a boronic acid (7). This reaction is carriedout in the presence of a palladium catalyst, for exampletetrakis(triphenylphosphine)-palladium according to the conditionsdescribed by N. Miyaura et al. Synthetic Communications (1981) 11(7),513-519. The boronic derivatives (7) may be obtained from thecorresponding halogenated (preferably iodinated or brominated)derivatives first of all by protection of the aldehyde functional groupin acetal form and then conversion to a lithium compound, reaction withtrimethyl or triisopropyl borate and hydrolysis in acidic medium(hydrochloric acid).

[0154] The halogenated derivatives (6) are obtained from thecorresponding primary amines. The latter are protected by coupling withdi-tert-butyl carbonate in a solvent such as dichloromethane. Theresulting carbamate is alkylated via the use of a base such as sodiumhydride and an alkyl halide in order to give the derivative (6). Thederivatives (1b) and (3b) may be obtained (FIG. 2) from the derivatives(8) by a succession of reactions according to the conditions describedby B. Hulin et al. J. Med. Chem. (1996) 39, 3897-3907.

[0155] When R₁ contains an acid functional group, the compounds areprepared by protecting R₁ with a protecting group of the alkyl, allyl,benzyl or tert-butyl type. The passage to the free form may be carriedout:

[0156] in the case of an alkyl protective group, by means of sodiumhydroxide or lithium hydroxide in an alcoholic solvent such as methanolor in THF;

[0157] in the case of an allyl protective group, by means of a catalystsuch as some transition metal complexes in the presence of a secondaryamine such as morpholine;

[0158] in the case of a benzyl protective group, by debenzylation in thepresence of hydrogen by means of catalyst such as palladium on carbon;

[0159] in the case of a tert-butyl type protective group by means oftrimethylsilane iodide.

[0160] The compounds according to the invention have PPARγ type receptoractivating properties. The expression activator of PPARγ type receptorsis understood to mean according to the invention any compound whichexhibits a percentage activation of the PPARγ receptors of at least 20%,at the concentration of 1 μM, in a transactivation test as described inExample 35.

[0161] The preferred compounds of the present invention have apercentage activation of the PPARγ receptors greater than or equal to40% and advantageously greater than or equal to 70%.

[0162] Preferably, the activator of the PPARγ type receptors isspecific, that is to say that it has a ratio of the percentageactivation of the PPARα receptors to the percentage activation of thePPARα receptors (calculated relative to a reference compound, Wy 14643,activating the PPARα receptors by 100%) greater than or equal to 3.Preferably, this ratio is greater than or equal to 5 and moreadvantageously greater than or equal to 10.

[0163] The affinity of the PPAR derivatives for the human PPARγ receptorwas also determined in a binding test as described in Example 36. Theexpression ligand for the PPARγ receptors is understood to mean anycompound according to the invention having a Kd value of less than 10000 nM. Preferably, the compounds according to the invention have a Kdvalue of less than 1000 nM and advantageously less than 100 nM.

[0164] The subject of the present invention is also the compounds offormula (I) as described above, as a medicament.

[0165] The compounds according to the invention are particularlysuitable in the fields of the following treatments:

[0166] 1) for treating dermatological conditions linked to akeratinization disorder related to cell differentiation andproliferation, in particular to treat acne vulgaris, comedo-type acne,polymorphic acne, acne rosacea, nodulocystic acne, acne conglobata,senile acne, secondary acne such as solar acne, acne medicamentosa oroccupational acne;

[0167] 2) for treating other types of keratinization disorders, inparticular ichtyosis, ichtyosiform states, Darrier's disease, keratosispalmaris et plantaris, leukoplasia and leukoplasiform states, cutaneousor mucosal (buccal) lichen;

[0168] 3) for treating other dermatological conditions with aninflammatory immunoallergic component, with or without cellproliferation disorder, and in particular all the forms of psoriasis,whether cutaneous, mucosal or ungual, and even psoriatic rheumatism, orcutaneous atopy, such as eczema or respiratory atopy or gingivalhypertrophy;

[0169] 4) for treating any dermal or epidermal proliferations whetherbenign or malignant, whether of viral origin or not, such as verrucavulgaris, verruca plana and epidermodysplasia verruciformis, oral orflorid papillomatoses, T lymphoma, and proliferations which may beinduced by ultraviolet radiation in particular in the case of baso- andspinocellular epitheliomas, and any precancerous skin lesions such askeratoacanthomas;

[0170] 5) for treating other dermatological disorders such as immunedermatoses such as lupus erythematosus, bullous immune diseases andcollagen diseases, such as scleroderma;

[0171] 6) in the treatment of dermatological or general conditions withan immunological component;

[0172] 7) in the treatment of skin disorders due to exposure to UVradiation and for repairing or combating skin aging, whetherphotoinduced or chronological or for reducing actinic keratoses andpigmentations, or any pathologies associated with chronologic or actinicaging, such as xerosis;

[0173] 8) for combating sebaceous function disorders such as acnehyperseborrhoear or simple seborrhoea;

[0174] 9) for preventing or treating cicatrization disorders, or forpreventing or repairing stretch marks;

[0175] 10) in the treatment of pigmentation disorders, such ashyperpigmentation, melasma, hypopigmentation or vitiligo;

[0176] 11) in the treatment of lipid metabolism conditions, such asobesity, hyperlipidaemia or non-insulin-dependent diabetes;

[0177] 12) in the treatment of inflammatory conditions such asarthritis;

[0178] 13) in the treatment or prevention of cancerous or precancerousstates;

[0179] 14) in the prevention or treatment of alopecia of differentorigins, in particular alopecia due to chemotherapy or to radiation;

[0180] 15) in the treatment of immune system disorders, such as asthma,diabetes mellitus type I, multiple sclerosis, or other selectivedysfunctions of the immune system; and

[0181] 16) in the treatment of conditions of the cardiovascular systemsuch as arterosclerosis or hypertension.

[0182] The subject of the present invention is also a pharmaceuticalcomposition comprising, in a physiologically acceptable medium, at leastone compound of formula (I) as defined above.

[0183] The subject of the present invention is also the use of thecompounds of formula (I) for manufacturing a composition intended forthe treatment of the abovementioned conditions, in particular forregulating and/or restoring skin lipid metabolism.

[0184] The administration of the composition according to the inventionmay be carried out enterally, parenterally, topically or ocularly.Preferably, the pharmaceutical composition is packaged in a formsuitable for application by the topical route.

[0185] By the enteral route, the composition may be provided in the formof tablets, gelatin capsules, sugar-coated tablets, syrups, suspensions,solutions, powders, granules, emulsions, suspensions of lipid orpolymeric microspheres or nanospheres or vesicles allowing controlledrelease. By the parenteral route, the composition may be provided in theform of solutions or suspensions for perfusion or injection.

[0186] Compounds according to the invention are generally administeredat a daily dose of about 0.001 mg/kg to 100 mg/kg of body weight, in 1to 3 doses.

[0187] The compositions are used by the systemic route at aconcentration generally of between 0.001% and 10% by weight, preferablybetween 0.01% and 1% by weight, relative to the weight of thecomposition.

[0188] By the topical route, the pharmaceutical composition according tothe invention is more particularly intended for the treatment of theskin and the mucous membranes and may be provided in the form of salves,creams, milks, ointments, powders, impregnated pads, solutions, gels,sprays, lotions or suspensions. It may also be provided in the form ofsuspensions of lipid or polymeric microspheres or nanospheres orvesicles or of polymeric patches and of hydrogels allowing controlledrelease. This composition for the topical route may be provided inanhydrous form, in aqueous form or in the form of an emulsion.

[0189] The compounds are used by the topical route at a concentrationwhich is generally between 0.001% and 10% by weight, preferably between0.01% and 1% by weight, relative to the total weight of the composition.

[0190] The compounds of formula (I) according to the invention also findapplication in the cosmetic field, and more particularly for regulatingand/or restoring skin lipid metabolism, in particular for preventingand/or treating the cutaneous signs of aging and/or of dry skin.

[0191] The subject of the invention is therefore also a compositioncomprising, in a cosmetically acceptable carrier, at least one of thecompounds of formula (I).

[0192] The subject of the invention is also the cosmetic use of thecompounds of formula (I) for body or hair hygiene.

[0193] The cosmetic composition according to the invention containing,in a cosmetically acceptable carrier, at least one compound of formula(I) or one of its optical or geometric isomers or one of its salts, maybe provided in particular in the form of a cream, a milk, a lotion, agel, suspensions of lipid or polymeric microspheres or nanospheres orvesicles, a soap or a shampoo.

[0194] The concentration of compound of formula (I) in the cosmeticcomposition is preferably between 0.001% and 3% by weight, relative tothe total weight of the composition.

[0195] The pharmaceutical and cosmetic compositions as described abovemay in addition contain inert additives, or even pharmacodynamicallyactive additives as regards the pharmaceutical compositions, orcombinations of these additives, and in particular:

[0196] wetting agents;

[0197] flavor enhancers;

[0198] preservatives such as esters of parahydroxybenzoic acid;

[0199] stabilizers;

[0200] moisture regulators;

[0201] pH regulators;

[0202] osmotic pressure modifiers;

[0203] emulsifiers;

[0204] UV-A and UV-B screening agents;

[0205] antioxidants, such as α-tocopherol, butylated hydroxyanisole orbutylated hydroxytoluene, Super Oxide Dismutase, Ubiquinol or certainmetal chelators;

[0206] depigmenting agents such as hydroquinone, azelaic acid, caffeicacid or kojic acid;

[0207] emollients;

[0208] moisturizing agents such as glycerol, PEG 400, thiamorpholinone,and its derivatives, or urea;

[0209] antiseborrhoeic or anti-acne agents, such asS-carboxymethylcysteine, S-benzylcysteamine, their salts or theirderivatives, or benzoyl peroxide;

[0210] antibiotics such as erythromycin and its esters, neomycin,clindamycin and its esters, tetracyclines;

[0211] antifungal agents such as ketoconazole or4,5-polymethylene-3-isothiazolidones;

[0212] agents promoting hair regrowth, such as Minoxidil(2,4-diamino-6-piperidinopyrimidine 3-oxide) and its derivatives,Diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine 1,1-dioxide) andPhenytoin (5,4-diphenylimidazolidine 2,4-dione);

[0213] nonsteroidal anti-inflammatory agents;

[0214] carotenoids and, in particular, β-carotene;

[0215] antipsoriatic agents such as anthralin and its derivatives;

[0216] 5,8,11,14-eicosatetraynoic and 5,8,11-eicosatriynoic acids, theiresters and amides;

[0217] retinoids, that is to say ligands for the RAR or RXR receptors,which may be natural or synthetic;

[0218] corticosteroids or oestrogens;

[0219] α-hydroxy acids and α-keto acids or their derivatives, such aslactic, malic, citric, glycolic, mandelic, tartaric, glyceric andascorbic acids, and their salts, amides or esters, or β-hydroxy acids ortheir derivatives, such as salicylic acid and its salts, amides oresters;

[0220] ion channel, such as potassium channel, blockers;

[0221] or alternatively, more particularly for pharmaceuticalcompositions, in combination with medicaments known to interfere withthe immune system (for example cyclosporine, FK 506, glucocorticoids,monoclonal antibodies, cytokines or growth factors, and the like).

[0222] Of course, persons skilled in the art will be careful to choosethe possible compound(s) to be added to these compositions such that theadvantageous properties intrinsically attached to the present inventionare not or not substantially impaired by the addition envisaged.

[0223] Several examples of production of active compounds of formula (I)according to the invention, results of biological activity and variousconcrete formulations based on such compounds, will now be given by wayof illustration and without being limiting in any manner.

EXAMPLE 1

[0224] methyl7-{[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamoyl}heptanoate

[0225] (a) tert-butyl (3-bromobenzyl)carbamate

[0226] 40.7 g (183 mmol) of 3-bromobenzylamine hydrochloride, 26 ml oftriethylamine (183 mmol) and 450 ml of dichloromethane are introducedinto a round-bottomed flask and under a nitrogen stream. 40 g (183 mmol)of di-tert-butyl dicarbonate are added in small quantities at roomtemperature and the mixture is stirred overnight. The reaction medium ispoured into ice-cold water, extracted with dichloromethane, the organicphase decanted off, dried over magnesium sulphate and evaporated off. 46g (88%) of the expected product are recovered.

[0227] (b) tert-butyl (3-bromobenzyl)-N-methylcarbamate

[0228] 128 g (447 mmol) of tert-butyl (3-bromobenzyl)carbamate and 800ml of DMF are introduced into a round-bottomed flask and under anitrogen stream. 19 g (475 mmol) of sodium hydride (60% in oil) areadded in small quantities and the mixture is stirred until the gasemission ceases. 29.3 ml (470 mmol) of methyl iodide are then added andthe mixture is stirred overnight. The reaction medium is poured intoice-cold water, extracted with ethyl acetate, the organic phase decantedoff, dried over magnesium sulphate and evaporated off. 152.5 g (92%) ofthe expected product are recovered.

[0229] (c) tert-butyl (4′-formylbiphenyl-3-ylmethyl)methylcarbamate

[0230] 61.5 g (205 mmol) of tert-butyl(3-bromobenzyl)-N-methylcarbamate, 40 g (260 mmol) of4-formylbenzeneboronic acid and 800 ml of toluene are introduced into athree-necked flask and under argon. 205 ml of an aqueous potassiumcarbonate solution (2 M) are added dropwise, the reaction medium isdegassed with argon and 7 g of tetrakis(triphenylphosphine)-palladium(0)chloride are added and the mixture is heated at 90° C. for 24 hours. Thereaction medium is poured into water, extracted with dichloromethane,the organic phase decanted off, dried over magnesium sulphate andevaporated off. The residue obtained is purified by chromatography on asilica column eluted with a heptane and ethyl acetate (70-30) mixture.After evaporation of the solvents, 38 g (57%) of the expected productare recovered.

[0231] (d) tert-butyl[4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-ylmethyl]methylcarbamate

[0232] 75.4 g (232 mmol) of tert-butyl(4′-formylbiphenyl-3-ylmethyl)methylcarbamate, 32.5 g (278 mmol) of2,4-thiazolidenedione, 7.3 g (50 mmol) of piperidine acetate and 11 oftoluene are introduced into a round-bottomed flask and under a nitrogenstream. The mixture is heated under reflux for five hours and the waterformed is separated with the aid of a Dean-Stark. The reaction medium iscooled, and the precipitate formed is filtered off. 84 g (86%) of theexpected product are recovered.

[0233] (e) tert-butyl[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamate

[0234] 30 g (70.7 mmol) of tert-butyl[4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-ylmethyl]methylcarbamatein 500 ml of dioxane are introduced into a three-necked flask. Thereaction medium is degassed, 30 g of palladium on carbon (10%) are addedand the mixture is hydrogenated at a pressure of 3 bar at 60° C. Thereaction medium is filtered, evaporated off and the residue obtained ispurified by chromatography on a silica column eluted with adichloromethane and methanol (99-1) mixture. 18 g (60%) of the expectedproduct are recovered after evaporation of the solvents.

[0235] (f)5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dione

[0236] 18 g (42 mmol) of tert-butyl[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamatein 250 ml of dichloromethane are introduced into a round-bottomed flaskand under a nitrogen stream, and 16 ml (208 mmol) of trifluoroaceticacid are added. The mixture is stirred at room temperature overnight andthe reaction medium is hydrolysed with a saturated potassium carbonatesolution. The mixture is extracted with dichloromethane, the organicphase decanted off, washed with water, dried over magnesium sulphate andevaporated off. The residue obtained is triturated in ethyl acetate and14.4 g (78%) of the expected product are obtained.

[0237] (g) methyl7-{[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamoyl}heptanoate

[0238] 600 mg (1.36 mmol) of5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dione, 10 mlof THF and 600 μl (4.3 mmol) of triethylamine are introduced into around-bottomed flask and under a nitrogen stream. 220 μl (1.55 mmol) ofmethyl 8-chloro-8-oxooctanoate are added dropwise and the mixture isstirred for one hour. The reaction medium is poured into water,extracted with dichloromethane, the organic phase decanted off, washedwith water, dried over magnesium sulphate and evaporated off. Theresidue obtained is purified by chromatography on a silica column elutedwith a dichloromethane and ethyl acetate (80-20) mixture. Afterevaporation of the solvents, 350 mg (50%) of methyl7-{[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamoyl}heptanoateare recovered in the form of an oil.

[0239]¹H NMR (CDCl₃): 0.88-1.40 (m, 4H); 1.62-1.70 (m, 4H); 2.31 (t,J=7.4 Hz, 2H); 2.40 (t, J=7.3 Hz, 2H); 2.96-2.99 (m, 3H); 3.15 (m, 1H);3.58 (m, 1H); 3.66 (s, 3H); 4.57 (m, 1H; 4.60-4.66 (m, 2H); 7.23-7.55(m, 8H); 9.15 (m, 1H).

EXAMPLE 2

[0240] methyl9-{[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamoyl}nonanoate

[0241] In a manner similar to Example 1(g), by reacting 600 mg (1.36mmol) of5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dioneobtained in l(f) with 340 μl (1.52 mmol) of methyl10-chloro-10-oxodecanoate, 500 mg (70%) of methyl9-{[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamoyl}nonanoateare obtained in the form of an oil after purification by chromatographyon a silica column eluted with a dichloromethane and ethyl acetate(80/20) mixture.

[0242]¹H NMR (CDCl₃): 1.26-1.32 (m, 8H); 1.59-1.65 (m, 4H); 2.20-2.43(m, 4H); 2.95-2.99 (m, 3H); 3.16 (m, 1H); 3.55 (m, 1H); 3.85 (s, 3H);4.54 (m, 1H); 4.60-4.65 (m, 2H); 7.19-7.54 (m, 8H); 9.75 (m, 1H).

EXAMPLE 3

[0243] methylN-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylterephthalamate

[0244] In a manner similar to Example 1(g), by reacting 600 mg (1.36mmol) of5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dioneobtained in 1(f) with 310 mg (1.54 mmol) of methyl4-chlorocarbonylbenzoate, 370 mg (60%) of methylN-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylterephthalamateare obtained in the form of a white solid having a melting point of 186°C. after purification by chromatography on a silica column eluted with adichloromethane and ethyl acetate (90/10) mixture.

EXAMPLE 4

[0245]3-cyclopentyl-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylpropionamide

[0246] In a manner similar to Example 1(g), by reacting 500 mg (1.13mmol) of5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dioneobtained in l(f) with 200 mg (1.30 mmol) of 3-cyclopentylpropionylchloride, 170 mg (25%) of3-cyclopentyl-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylpropionamideare obtained in the form of a solid after purification by chromatographyon a silica column eluted with a dichloromethane and methanol (99/1)mixture.

[0247]¹H NMR (CDCl₃): 1.10-1.14 (m, 2H); 1.26 (t, J=7.1 Hz, 3H);1.50-1.79 (m, 6H); 2.42 (t, J=7.6 Hz, 2H); 2.97 (m, 3H); 3.15 (m, 1H);3.58 (m, 1H); 4.52 (m, 1H); 4.61-4.66 (m, 2H); 7.20-7.55 (m, 8H); 9.48(s, 1H).

EXAMPLE 5

[0248]N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-1-carboxamide

[0249] In a manner similar to Example 1(g), by reacting 1 g (2.3 mmol)of 5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dioneobtained in l(f) with 380 μl (2.5 mmol) of 1-naphthoyl chloride, 460 mg(41%) ofN-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-1-carboxamideare obtained in the form of a white solid having a melting point of 120°C. after purification by chromatography on a silica column eluted with aheptane and ethyl acetate (80/20) mixture.

EXAMPLE 6

[0250]N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide

[0251] In a manner similar to Example 1(g), by reacting 1 g (2.3 mmol)of 5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dioneobtained in 1(f) with 480 mg (2.5 mmol) of 2-naphthoyl chloride, 400 mg(40%) ofN-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamideare obtained in the form of a solid having a melting point of 218° C.after purification by chromatography on a silica column eluted with aheptane and ethyl acetate (70/30) mixture.

EXAMPLE 7

[0252]N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-2-phenoxyacetamide

[0253] In a manner similar to Example l(g), by reacting 500 mg (1.53mmol) of5-(3′-methylamino-methylbiphenyl-4-ylmethyl)thiazolidine-2,4-dioneobtained in l(f) with 210 μl (1.52 mmol) of phenoxyacetyl chloride, 640mg (91%) ofN-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-2-phenoxyacetamideare obtained in the form of a white solid having a melting point of 140°C. after purification by chromatography on a silica column eluted with aheptane and ethyl acetate (60/40) mixture.

EXAMPLE 8

[0254]N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-1-methyl-1H-pyrrole-2-carboxamide

[0255] (a) 1-Methyl-1H-pyrrole-2-carboxylic acid chloride

[0256] 500 mg (4 mmol) of 1-methyl-2-pyrrolecarboxylic acid in 5 ml ofdichloromethane are introduced into a round-bottomed flask and under anitrogen stream. There are added, dropwise, 790 μl (4 mmol) ofdicyclohexylamine and, 30 minutes later, 290 μl (4 mmol) of thionylchloride. The medium is stirred for 1 hour at room temperature and thenheated for 2 hours at 50° C. The mixture is then diluted with ether andthe precipitate is filtered off. The filtrate is evaporated off and abrown oil is obtained.

[0257] (b)N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-1-methyl-1H-pyrrole-2-carboxamide

[0258] In a manner similar to Example 1(g), by reacting 500 mg (1.53mmol) of5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dioneobtained in 1(f) with 220 mg (1.53 mmol) of1-methyl-1H-pyrrole-2-carboxylic acid chloride, 316 mg (47%) ofN-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-1-methyl-1H-pyrrole-2-carboxamideare obtained in the form of a white solid having a melting point of 184°C. after purification by chromatography on a silica column eluted with aheptane and ethyl acetate (60/40) mixture.

EXAMPLE 9

[0259]N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyladamantane-1-carboxamide

[0260] In a manner similar to Example 1(g), by reacting 500 mg (1.53mmol) of5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dioneobtained in 1(f) with 310 mg (1.56 mmol) of adamantane-1-carboxylic acidchloride, 390 mg ofN-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyladamantane-1-carboxamideare obtained in the form of a white powder having a melting point of 77°C. after purification by chromatography on a silica column eluted with aheptane and ethyl acetate (70/30) mixture.

EXAMPLE 10

[0261]N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbiphenyl-4-carboxamide

[0262] In a manner similar to Example 1(g), by reacting 500 mg (1.53mmol) of5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dioneobtained in 1(f) with 330 mg (1.52 mmol) of 4-biphenylcarboxylic acidchloride, 681 mg (88%) ofN-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbiphenyl-4-carboxamideare obtained in the form of a white powder having a melting point of204° C. after trituration in ether.

EXAMPLE 11

[0263]N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbenzo[b]thio-phene-2-carboxamide

[0264] In a manner similar to Example 1(g), by reacting 500 mg (1.53mmol) of5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dioneobtained in l(f) with 300 mg (1.52 mmol) ofbenzo[b]thiophene-2-carboxylic acid chloride, 509 mg (68%) ofN-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbenzo[b]thio-phene-2-carboxamideare obtained in the form of a white powder having a melting point of187° C. after trituration in dichloromethane.

EXAMPLE 12

[0265]N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-6-oxo-6-phenylhexanamide

[0266] 320 mg (1.55 mmol) of 5-benzoylpentanoic acid in 5 ml ofdichloromethane are introduced into a round-bottomed flask and under anitrogen stream. 230 mg (1.7 mmol) of 1-hydroxybenzotriazole hydrate,230 μl (1.7 mmol) of triethylamine and 500 mg (1.53 mmol) of5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dioneobtained in 1(f) are added. Next, at 0° C., 320 mg (1.7 mmol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added.The medium is stirred for 3 hours at room temperature. It is dilutedwith dichloromethane and washed with a saturated aqueous sodium hydrogencarbonate solution. The organic phase is dried over magnesium sulphate,filtered and evaporated off. The residue is purified by chromatographyon a silica column eluted with a heptane and ethyl acetate (50/50)mixture. 590 mg (75%) ofN-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-6-oxo-6-phenylhexanamideare obtained in the form of a white powder having a melting point of 48°C.

EXAMPLE 13

[0267]4-dimethylamino-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-1-carboxamide

[0268] In a manner similar to Example 12, by reacting 500 mg (1.53 mmol)of 5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dioneobtained in l(f) with 330 mg (1.53 mmol) of4-dimethylaminonaphthalene-1-carboxylic acid, 520 mg (65%) of4-dimethylamino-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-1-carboxamideare obtained in the form of a yellowish foam having a melting point of67° C. after purification by chromatography on a silica column elutedwith a heptane and ethyl acetate (50/50) mixture.

EXAMPLE 14

[0269]N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-4-methanesulphonyl-N-methylbenzamide

[0270] In a manner similar to Example 12, by reacting 500 mg (1.53 mmol)of 5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dioneobtained in l(f) with 310 mg (1.55 mmol) of 4-(methylsulphonyl)benzoicacid, 540 mg (69%) ofN-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-4-methanesulphonyl-N-methylbenzamideare obtained in the form of a white solid having a melting point of 172°C. after purification by chromatography on a silica column eluted with adichloromethane and methanol (98/2) mixture.

EXAMPLE 15

[0271]N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4-(1-phenylmethanoyl)benzamide

[0272] (a) 4-(1-phenylmethanoyl)benzoyl chloride

[0273] In a manner similar to Example 9(a), starting with 500 mg (2.2mmol) of 4-benzoylbenzoic acid, 490 mg (91%) of the expected product areobtained in the form of a white solid.

[0274] (b)N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4-(1-phenylmethanoyl)benzamide

[0275] In a manner similar to Example 1(g), by reacting 500 mg (1.53mmol) of5-(3′-methylaminomethyl-biphenyl-4-ylmethyl)thiazolidine-2,4-dioneobtained in 1(f) with 380 mg (1.55 mmol) of 4-(1-phenylmethanoyl)benzoylchloride, 660 mg (81%) ofN-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4-(1-phenylmethanoyl)benzamideare obtained in the form of a white powder having a melting point of 94°C. after purification by chromatography on a silica column eluted with aheptane and ethyl acetate (50/50) mixture.

EXAMPLE 16

[0276]6-(2-methoxyethoxymethoxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnapthalene-2-carboxamide

[0277] (a) methyl 6-hydroxynaphthalene-2-carboxylate.

[0278] 15.7 g (83 mmol) of 6-hydroxy-2-naphthoic acid in 160 ml ofmethanol are introduced into a round-bottomed flask. 8 ml ofconcentrated sulphuric acid are added and the mixture is heated underreflux for 8 hours. At room temperature, a precipitate forms. It isfiltered off, rinsed with ether and dried. 14.1 g (84%) of the expectedproduct are obtained in the form of a beige powder.

[0279] (b) methyl 6-(2-methoxyethoxymethoxy)naphthalene-2-carboxylate

[0280] 14 g (69 mmol) of methyl 6-hydroxynaph-thalene-2-carboxylate in90 ml of dimethylformamide and 90 ml of tetrahydrofuran are introducedinto a round-bottomed flask and under a nitrogen stream. 3.3 g (82 mmol)of sodium hydride at 60% are added in small portions. When the gasemission has ceased, 8.7 ml (76 mmol) of 2-methoxyethoxymethyl chlorideare added and the reaction medium is stirred for 3 hours at roomtemperature. It is then poured into ice-cold water and extracted withether. The organic phase is dried over magnesium sulphate, filtered andevaporated off. The residue obtained is purified by chromatography on asilica column eluted with a heptane and ethyl acetate (80/20) mixtureand 17 g (85%) of the expected product are obtained in the form of acolorless oil.

[0281] (c) 6-(2-methoxyethoxymethoxy)naphthale-2-carboxylic Acid

[0282] 16.9 g (58 mmol) of methyl6-(2-methoxyethoxymethoxy)naphthalene-2-carboxylate in 200 ml oftetrahydrofuran and 20 ml of methanol are introduced into around-bottomed flask. 1 ml of water and 12.9 g (322 mmol) of sodiumhydroxide pellets are added. The reaction medium is stirred for 4 hoursat room temperature. 1N hydrochloric acid is slowly added in the coldstate up to pH 2-3. The mixture is extracted with ethyl acetate. Theorganic phase is dried over magnesium sulphate, filtered and thenevaporated off. The residue is triturated in heptane, filtered anddried. 14.9 g (92%) of the expected product are obtained in the form ofa white powder having a melting point of 110° C.

[0283] (d) 6-(2-methoxyethoxymethoxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide

[0284] In a manner similar to Example 12, by reacting 1.5 g (4.6 mmol)of 5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dioneobtained in 1(f) with 1.27 g (4.6 mmol) of6-(2-methoxyethoxymethoxy)naphthalene-2-carboxylic acid, 1.97 g (62%) of6-(2-methoxyethoxymethoxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamideare obtained in the form of a white powder having a melting point of 68°C. after purification by chromatography on a silica column eluted with aheptane and ethyl acetate (50/50) mixture.

EXAMPLE 17

[0285]6-hydroxy-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide

[0286] 1.5 g (2.5 mmol) of6-(2-methoxyethoxymethoxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide(obtained in Example 16) in 10 ml of tetrahydrofuran and 10 ml ofmethanol are introduced into a round-bottomed flask. 500 μl ofconcentrated sulphuric acid are added and the medium is stirred for 2hours at room temperature. Water is added and the mixture is extractedwith ethyl acetate. The organic phase is dried over magnesium sulphate,filtered and then evaporated off. The residue is purified bychromatography on a silica column eluted with a heptane and ethylacetate (30/70) mixture. 1.26 g (99%) of6-hydroxy-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamideare obtained in the form of a white powder having a melting point of218° C.

EXAMPLE 18

[0287]N-[4′-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4-methylsulphanylbenzamide

[0288] (a) 4-methylsulphanylbenzoyl chloride

[0289] In a manner similar to Example 9(a), starting with 400 mg (2.4mmol) of 4-(methylthio)benzoic acid, 440 mg (99%) of the expectedproduct are obtained in the form of a yellowish solid.

[0290] (b)N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-methyl]-N-methyl-4-methylsulphanylbenzamide

[0291] In a manner similar to Example 1(g), by reacting 500 mg (1.53mmol) of5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dioneobtained in 1(f) with 290 mg (1.55 mmol) of 4-methylsulphanylbenzoylchloride, 470 mg (64%) ofN-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4-methylsulphanylbenzamideare obtained in the form of a white powder having a melting point of203-7° C. after recrystallization from methanol.

EXAMPLE 19

[0292](S)-3-(3′-{[(1-biphenyl-4-ylmethanoyl)methylamino]methyl}biphenyl-4-yl)-2-ethoxypropionicAcid

[0293] (a) ethoxyacetyl chloride

[0294] 25 g (240 mmol) of ethoxyacetic acid in 300 ml of dichloromethaneare introduced into a round-bottomed flask and under a nitrogen stream.47.6 ml (239 mmol) of dicyclohexylamine are added. The medium is stirredfor 1 hour at room temperature. 19.2 ml (265 mmol) of thionyl chlorideare added and the mixture is stirred for 3 hours. Ethyl ether is addedto the reaction medium, the precipitate formed is filtered off andrinsed with ether. After evaporation of the filtrate, 29 g (100%) of theexpected product are obtained in the form of a brown liquid.

[0295] (b) 3-(2-ethoxyethanoyl)-4-benzyloxazolidin-2-one

[0296] 36.7 g (207 mmol) of (S)-4-benzyloxazolidin-2-one in 800 ml ofTHF are introduced into a round-bottomed flask and under a nitrogenstream. The reaction medium is cooled to −78° C. and 83 ml (207 mmol) ofn-butyllithium (2.5 M/hexane) are added dropwise. 30 minutes later, 25.4g (207 mmol) of ethoxyacetyl chloride are added at −78° C. The reactionmedium is stirred for 24 hours and then poured into a saturated aqueoussodium chloride solution and extracted with ethyl acetate. The organicphase is dried over magnesium sulphate, filtered and evaporated off.30.6 g (56%) of the expected product are obtained in the form of anorange-colored oil after purification by chromatography on a silicacolumn eluted with a heptane and ethyl acetate (60/40) mixture.

[0297] (c) methyl(2S,3R)-3-{3′-[(tert-butoxycarbonylmethylamino)methyl]biphenyl-4-yl}-2-ethoxy-3-hydroxypropionate

[0298] 21.9 g (83 mmol) of 3-(2-ethoxyethanol)-4-benzyloxazolidin-2-oneand 100 ml of dichloromethane are introduced into a round-bottomed flaskand under argon. 103 ml (103 mmol) of dibutylboranetrifluoromethanesulphonate and 18 ml (104 mmol) of 47N-ethyldiisopropylamine are successively added, at 0° C., dropwise, andthe mixture is stirred for one hour. At −78° C., a solution of 23.5 g(69 mmol) of tert-butyl (4′-formylbiphenyl-3-ylmethyl)methylcarbamateobtained in 1(c) in 100 ml of dichloromethane is added and the mixtureis stirred overnight. It is treated with a buffer solution pH=7 (170 ml)in 500 ml of methanol and then with a solution of hydrogen peroxide (170ml) in 500 ml of methanol and the mixture is stirred for 1 hour 30minutes at 0° C. The reaction medium is poured into water, and extractedwith dichloromethane. The organic phase is dried over magnesiumsulphate, filtered and evaporated off. The residue obtained is purifiedby chromatography on a silica column eluted with a heptane and ethylacetate (70/30) mixture and 21 g (51%) of the expected product areobtained.

[0299] (d) methyl(2S,3R)-2-ethoxy-3-hydroxy-3-(3′-methylaminomethylbiphenyl-4-yl)propionate

[0300] 21 g (47.3 mmol) of methyl(2S,3R)-3-{3′-[(tert-butoxycarbonylmethylamino)methyl]biphenyl-4-yl}-2-ethoxy-3-hydroxypropionate,8.76 ml (54.9 mmol) of triethylsilane in 300 ml of trifluoroacetic acidare introduced into a round-bottomed flask and under a nitrogen stream.The reaction medium is stirred for 4 hours at room temperature. Ethylacetate is then added and the mixture is neutralized with sodiumhydroxide. The organic phase is washed with a saturated aqueous sodiumchloride solution, dried over magnesium sulphate, filtered andevaporated off. 19.6 g (100%) of the expected crude product areobtained.

[0301] (e) methyl(S)-2-ethoxy-3-(3′-methylaminomethylbiphenyl-4-yl)propionate

[0302] 19.6 g of the crude product methyl(2S,3R)-2-ethoxy-3-hydroxy-3-(3′-methylaminomethylbiphenyl-4-yl)propionateare dissolved in 200 ml of trifluoroacetic acid and 41.7 ml (297 mmol)of triethylamine are added. The reaction medium is stirred at roomtemperature for 48 hours and then extracted with ethyl acetate. Theorganic phase is decanted off, washed with a sodium hydroxide solutionand then with a saturated aqueous sodium chloride solution, dried overmagnesium sulphate, filtered and evaporated off. The residue obtained ispurified by chromatography on a silica column eluted with adichloromethane and methanol (95/5) mixture. 1.6 g (10%) of the expectedproduct are obtained.

[0303] (f) methyl(S)-3-(3′-{[(1-biphenyl-4-ylmethanoyl)methylamino]methyl}biphenyl-4-yl)-2-ethoxypropionate

[0304] In a manner similar to Example 1(g), by reacting 500 mg (1.5mmol) of methyl(S)-2-ethoxy-3-(3′-methylaminomethylbiphenyl-4-yl)propionate with 680 mg(3.1 mmol) of 4-biphenylcarboxylic acid chloride, 360 mg (47%) of theexpected product are obtained after purification by chromatography on asilica column eluted with a heptane and ethyl acetate (70/30) mixture.

[0305] (g)(S)-3-(3′-{[(1-biphenyl-4-ylmethanoyl)methylamino]methyl}biphenyl-4-yl)-2-ethoxypropionicAcid

[0306] 360 mg (0.7 mmol) of methyl(S)-3-(3′-{[(1-biphenyl-4-ylmethanoyl)methylamino]methyl}biphenyl-4-yl)-2-ethoxypropionatein 10 ml of THF are introduced into a round-bottomed flask. 60 mg (1.4mmol) of lithium hydroxide monohydrate, 1 ml of water and 1 ml ofmethanol are added and the mixture is stirred for 4 hours. The reactionmedium is poured into water, acidified to pH 1, extracted with ethylacetate, the organic phase decanted off, dried over magnesium sulphateand evaporated off. The residue obtained is purified by chromatographyon a silica column eluted with a heptane and ethyl acetate (50/50)mixture and 280 mg (80%) of(S)-3-(3′-{[(1-biphenyl-4-ylmethanoyl)methylamino]methyl}biphenyl-4-yl)-2-ethoxypropionicacid are obtained in the form of an amorphous white solid.

[0307]¹H NMR (CDCl₃): 1.19 (t, J=8 Hz, 3H); 2.96-3.09 (m, 3H); 3.05 (dd,J=14.1 Hz and J=7.8 Hz, 1H); 3.17 (dd, J=14.1 Hz and J=4 Hz, 1H);3.45-3.61 (m, 2H); 4.12 (m, 1H); 4.64-4.84 (m, 2H); 7.25-7.56 (m, 17H).

EXAMPLE 20

[0308](S)-2-ethoxy-3-(3′-{[methyl(6-oxo-6-phenylhexanoyl)amino]methyl}biphenyl-4-yl)propionicAcid

[0309] (a) methyl(S)-2-ethoxy-3-(3′-{[methyl(6-oxo-6-phenylhexanoyl)amino]methyl}biphenyl-4-yl)propionate

[0310] In a manner similar to Example 12, by reacting 660 mg (2 mmol) ofmethyl (S)-2-ethoxy-3-(3′-methylaminomethylbiphenyl-4-yl)propionateobtained in 19(e) with 346 mg (1.68 mmol) of 5-benzoylpentanoic acid,330 mg (33%) of the expected product are obtained after purification bychromatography on a silica column eluted with a heptane and ethylacetate (50/50) mixture.

[0311] (b)(S)-2-ethoxy-3-(3′-{[methyl(6-oxo-6-phenylhexanoyl)amino]methyl}biphenyl-4-yl)propionicAcid

[0312] In a manner similar to Example 19(g), starting with 330 mg (0.64mmol) of methyl(S)-2-ethoxy-3-(3′-{[methyl(6-oxo-6-phenylhexanoyl)amino]methyl}biphenyl-4-yl)propionate,230 mg (72%) of(S)-2-ethoxy-3-(3′-{[methyl(6-oxo-6-phenylhexanoyl)amino]methyl}biphenyl-4-yl)propionicacid are obtained in the form of a yellow oil after purification bychromatography on a silica column.

[0313]¹H NMR (CDCl₃): 1.20 (m, 3H); 1.77-1.85 (m, 4H); 2.44 (m, 2H);2.95-2.98 (m, 3H); 3.01 (m, 2H); 3.05 (m, 1H);.51 3.15 (m, 1H);3.46-3.61 (m, 2H); 4.10 (2s, 1H); 4.59-4.64 (m, 2H); 7.18-7.55 (m, 11H);7.90-7.96 (m, 2H).

EXAMPLE 21

[0314]1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-1-methyl-3-naphthalen-2-ylurea

[0315] (a) (3-bromophenyl)methylamine

[0316] 10 g (58 mmol) of 3-bromoaniline and 34 ml (204 mmol) oftriethylorthoformate are introduced into a round-bottomed flask andunder a nitrogen stream. The reaction medium is heated under reflux for7 hours. The triethylorthoformate is then evaporated off. The residue isdissolved in ethanol and 4.9 g (12.8 mmol) of sodium borohydride areadded at 0° C. The medium is stirred overnight at room temperature. Itis then poured into water and extracted with ethyl acetate. The organicphase is washed with a saturated aqueous sodium chloride solution, driedover magnesium sulphate, filtered and then evaporated off. The residueobtained is purified by chromatography on a silica column eluted with aheptane and ethyl acetate (90/10) mixture and 5 g (46%) of the expectedproduct are obtained in the form of a light oil.

[0317] (b) 3′-methylaminobiphenyl-4-carbaldehyde

[0318] In a manner similar to Example 1(c), by reacting 4.3 g (23.2mmol) of (3-bromophenyl)methylamine with 5.2 g (34.8 mmol) of4-formylbenzeneboronic acid, 2.9 g (59%) of the expected product areobtained in the form of a yellow solid after purification bychromatography on a silica column eluted with a heptane and ethylacetate (90/10) mixture.

[0319] (c)5-(3′-methylaminobiphenyl-4-ylmethylene)thiazolidine-2,4-dione

[0320] In a manner similar to Example 1(d), by reacting 2.9 g (13.7mmol) of 3′-methylaminobiphenyl-4-carbaldehyde with 1.6 g (13.7 mmol) of2,4-thiazolidinedione, 3.9 g (91%) of the expected product are obtainedafter trituration in dichloromethane and ether.

[0321] (d)1-[4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-yl]-1-methyl-3-naphthalen-2-ylurea

[0322] 500 mg (1.6 mmol) of5-(3′-methylaminobiphenyl-4-ylmethylene)thiazolidine-2,4-dione in 10 mlof dichloromethane and 540 mg (3.2 mmol) of naphthyl isocyanate areintroduced into a round-bottomed flask and under a nitrogen stream. Themixture is stirred at 35° C. for 4 hours. The reaction medium isfiltered and the solid is rinsed with dichloromethane. The filtrate isevaporated off and 660 mg (86%) of the expected product are obtained inthe form of a yellow powder.

[0323] (e)1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-1-methyl-3-naphthalen-2-ylurea

[0324] In a manner similar to Example 1(e), starting with 660 mg (1.38mmol) of1-[4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-yl]-1-methyl-3-naphthalen-2-ylurea,320 mg (48%) of1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-1-methyl-3-naphthalen-2-ylureaare obtained in the form of a white powder having a melting point of196° C. after purification by chromatography on a silica column elutedwith a heptane and ethyl acetate (70/30) mixture.

EXAMPLE 22

[0325]3-(4-dimethylaminophenyl)-1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-1-methylurea

[0326] (a)3-(4-dimethylaminophenyl)-1-[4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-yl]-1-methylurea

[0327] In a manner similar to Example 22(d), by reacting 500 mg (1.6mmol) of 5-(3′-methylaminobiphenyl-4-ylmethylene)thiazolidine-2,4-dioneobtained in 21(c) with 520 mg (3.2 mmol) of 4-(dimethylamino)phenylisocyanate, 760 mg (100%) of the expected product are obtained in theform of a yellow powder.

[0328] (b) 3-(4-dimethylaminophenyl)-1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-1-methylurea

[0329] In a manner similar to Example 1(e), starting with 760 mg (1.6mmol) of3-(4-dimethylaminophenyl)-1-[4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-yl]-1-methylurea,330 mg (43%) of3-(4-dimethylaminophenyl)-1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-1-methylureaare obtained in the form of a white powder having a melting point of102° C. after purification by chromatography on a silica column elutedwith a heptane and ethyl acetate (60/40) mixture.

EXAMPLE 23

[0330](S)-2-ethoxy-3-{3′-[({1-[6-(2-methoxyethoxymethoxy)naphthalen-2-yl]methanoyl}methylamino)methyl]biphenyl-4-yl}propionicacid

[0331] (a)(S)-2-ethoxy-3-{3′-[({1-[6-(2-methoxyethoxymethoxy)naphthalen-2-yl]methanoyl}methylamino)methyl]biphenyl-4-yl}propionicacid

[0332] In a manner similar to Example 13, by reacting 380 mg (1.16 mmol)of methyl (S)-2-ethoxy-3-(3′-methylaminomethylbiphenyl-4-yl)propionateobtained in 19(e) with 350 mg (1.27 mmol) of 6-(2-methoxy-ethoxymethoxy)naphthalene-2-carboxylic acid (prepared in 16(c)), 110 mg (16%) of theexpected product are obtained after purification by chromatography on asilica column eluted with a heptane and ethyl acetate (50/50) mixture.

[0333] (b)(S)-2-ethoxy-3-{3′-[({1-[6-(2-methoxyethoxymethoxy)naphthalen-2-yl]methanoyl}-methylamino)methyl]biphenyl-4-yl}propionic Acid

[0334] In a manner similar to Example 19(g), by reacting 110 mg (0.18mmol) of methyl(S)-2-ethoxy-3-{3′-[({1-[6-(2-methoxyethoxymethoxy)naphthalen-2-yl]methanoyl}methylamino)methyl]biphenyl-4-yl}propionatewith 16 mg (0.38 mmol) of lithium hydroxide monohydrate, 30 mg (42%) of(S)-2-ethoxy-3-{3′[({1-[6-(2-methoxyethoxymethoxy)naphthalen-2-yl]methanoyl}methylamino)methyl]biphenyl-4-yl}propionicacid are obtained in the form of a yellow oil after purification bychromatography on a silica column eluted with a heptane and ethylacetate (50/50) mixture then with pure ethyl acetate.

[0335]¹H NMR (CDCl₃): 1.18 (t, J=6.9 Hz, 3H); 2.90-3.17 (m, 5H); 3.37(s, 3H); 3.44-3.64 (m, 4H); 3.86 (m, 2H); 4.11 (m, 11H); 4.70 (m, 2H);5.39 (s, 2H); 7.23-7.54 (m, 11H); 7.75 (m, 2H); 7.91 (s, 1H).

EXAMPLE 24

[0336]6-(methoxymethoxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide

[0337] In a manner similar to Example 12, by reacting 500 mg (1.53 mmol)of 5-(3′-methylamino-methylbiphenyl-4-ylmethyl)thiazolidine-2,4-dioneobtained in l(f) with 371 mg (1.6 mmol) of6-methoxymethoxynaphthalene-2-carboxylic acid, 648 mg (75%) of6-(methoxymethoxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamideare obtained in the form of a white powder having a melting point of160° C. after purification by chromatography on a silica column elutedwith a heptane and ethyl acetate (50/50) mixture.

[0338]¹H NMR (DMSO d6; 400 MHz): 2.96 (broad s, 3H); 3.19 (dd, J=9.2 Hzand J=14.1 Hz, 1H); 3.41 (s, 3H); 3.44 (dd, J=4.2 Hz and J=14.1 Hz, 1H);4.58-4.82 (m, 2H); 4.97 (dd, J=4.3 Hz and J=9.1 Hz, 1H); 7.25-8.03 (m,14H); 12.10 (broad s, 1H)

EXAMPLE 25

[0339]6-(methoxycarbonyl)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide

[0340] In a manner similar to Example 12, by reacting 500 mg (1.53 mmol)of 5-(3′-methylamino-methylbiphenyl-4-ylmethyl)thiazolidine-2,4-dioneobtained in l(f) with 370 mg (1.6 mmol) of6-methoxycarbonylnaphthalene-2-carboxylic acid, 580 mg (67%) of6-(methoxycarbonyl)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamideare obtained in the form of a white powder having a melting point of125-127° C. after purification by chromatography on a silica columneluted with a heptane and ethyl acetate (50/50) mixture.

[0341]¹H NMR (DMSO d6; 400 MHz): 2.92-3.01 (m, 3H); 3.18 (m, 1H); 3.44(m, 1H); 3.93 (s, 3H); 4.59-4.80 (m, 2H); 4.97 (m, 1H); 7.20-7.70 (m,9H); 8.00-8.20 (m, 3H); 8.23 (m, 1H); 8.69 (m, 1H); 12.10 (broad s, 1H).

EXAMPLE 26

[0342]6-(propyloxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide

[0343] In a manner similar to Example 12, by reacting 500 mg (1.53 mmol)of 5-(3′-methylamino-methylbiphenyl-4-ylmethyl)thiazolidine-2,4-dioneobtained in 1(f) with 370 mg (1.6 mmol) of6-propyloxynaphthalene-2-carboxylic acid, 530 mg (61%) of6-(propyloxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamideare obtained in the form of a white powder having a melting point of108-110° C. after purification by chromatography on a silica columneluted with a heptane and ethyl acetate (50/50) mixture.

[0344]¹H NMR (DMSO d6; 400 MHz): 1.00 (t, J 7.4 Hz, 3H); 1.80 (m, 2H);2.96 (broad s, 3H); 3.17 (dd, J=9.2 Hz and J=14.1 Hz, 1H); 3.44 (dd,J=4.2 Hz and J=14.1 Hz, 1H); 4.06 (t, J=6.5 Hz, 2H); 4.63-4.77 (m, 2H);4.96 (dd, J=4.3 Hz and J=9.1 Hz, 1H); 7.19-7.98 (m, 14H); 12.10 (broads, 1H).

EXAMPLE 27

[0345]6-(hexyloxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide

[0346] In a manner similar to Example 12, by reacting 500 mg (1.53 mmol)of 5-(3′-methylamino-methylbiphenyl-4-ylmethyl)thiazolidine-2,4-dioneobtained in 1(f) with 436 mg (1.6 mmol) of6-hexyloxynaphthalene-2-carboxylic acid, 520 mg (56%) of6-(hexyloxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamideare obtained in the form of a white powder having a melting point of117° C. after purification by chromatography on a silica column elutedwith a heptane and ethyl acetate (60/40) mixture.

[0347]¹H NMR (DMSO d6; 400 MHz): 0.88 (m, 3H); 1.32 (m, 4H); 1.44 (m,2H); 1.79 (m, 2H); 2.96 (broad s, 3H); 3.17 (dd, J=9.2 Hz and J=14.1 Hz,1H); 3.44 (dd, J=4.2 Hz and J=14.1 Hz, 1H); 4.09 (t, J=6.5 Hz, 2H);4.63-4.77 (m, 2H); 4.96 (dd, J=4.3 Hz and J=9.1 Hz, 1H); 7.19-7.98 (m,14H); 12.10 (broad s, 1H).

EXAMPLE 28

[0348]6-(nonyloxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide

[0349] In a manner similar to Example 12, by reacting 500 mg (1.53 mmol)of 5-(3′-methylamino-methylbiphenyl-4-ylmethyl)thiazolidine-2,4-dioneobtained in 1(f) with 503 mg (1.6 mmol) of6-nonyloxynaphthalene-2-carboxylic acid, 590 mg (59%) of6-(nonyloxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamideare obtained in the form of a white powder having a melting point of117° C. after purification by chromatography on a silica column elutedwith a heptane and ethyl acetate (60/40) mixture.

[0350]¹H NMR (DMSO d6; 400 MHz): 0.85 (m, 3H); 1.20-1.40 (m, 10H); 1.45(m, 2H); 1.78 (m, 2H); 2.96 (broad s, 3H); 3.17 (dd, J=9.2 Hz and J=14.1Hz, 1H); 3.44 (dd, J=4.2 Hz and J=14.1 Hz, 1H); 4.09 (t, J=6.5 Hz, 2H);4.63-4.77 (m, 2H); 4.96 (dd, J=4.3 Hz and J=9.1 Hz, 1H); 7.19-7.98 (m,14H); 12.10 (broads, 1H).

EXAMPLE 29

[0351]N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4′-propylbiphenyl-2-carboxamide

[0352] In a manner similar to Example 12, by reacting 500 mg (1.53 mmol)of 5-(3′-methylamino-methylbiphenyl-4-ylmethyl)thiazolidine-2,4-dioneobtained in l(f) with 384 mg (1.6 mmol) of 4-(4′-propylphenyl)benzoicacid, 602 mg (68%) ofN-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4′-propylbiphenyl-2-carboxamideare obtained in the form of a white powder after purification bychromatography on a silica column eluted with a heptane and ethylacetate (60/40) mixture.

[0353]¹H NMR (DMSO d6; 400 MHz): 0.91 (t, J=7.3 Hz, 3H); 1.72 (m, 2H);2.58 (m, 2H); 2.93 (broad s, 3H); 3.19 (dd, J=9.2 Hz and J=14.1 Hz, 1H);3.43 (dd, J=4.2 Hz and J=14.1 Hz, 1H); 4.58-4.78 (m, 2H); 4.96 (dd,J=4.3 Hz and J=9.1 Hz, 1H); 7.20-7.75 (m, 16H); 12.10 (broad s, 1H).

EXAMPLE 30

[0354]N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4-phenoxybenzamide

[0355] In a manner similar to Example 12, by reacting 500 mg (1.53 mmol)of 5-(3′-methylamino-methylbiphenyl-4-ylmethyl)thiazolidine-2,4-dioneobtained in 1(f) with 343 mg (1.6 mmol) of 4-phenoxybenzoic acid, 545 mg(68%) ofN-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4-phenoxybenzamideare obtained in the form of a white powder having a melting point of 95°C. after purification by chromatography on a silica column eluted with aheptane and ethyl acetate mixture in a polarity gradient from (80/20) to(60/40).

EXAMPLE 31

[0356]N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-7-oxo-7-phenylheptanamide

[0357] In a manner similar to Example 12, by reacting 500 mg (1.53 mmol)of 5-(3′-methylamino-methylbiphenyl-4-ylmethyl)thiazolidine-2,4-dioneobtained in 1(f) with 352 mg (1.6 mmol) of 6-benzoylhexanoic acid, 610mg (75%) ofN-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-7-oxo-7-phenylheptanamideare obtained in the form of a white powder having a melting point of55-56° C. after purification by chromatography on a silica column elutedwith a heptane and ethyl acetate mixture in a polarity gradient from(70/30) to (50/50).

EXAMPLE 32

[0358]4′-(2-methoxyethoxymethoxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbiphenyl-4-carboxamide

[0359] (a) methyl 4′-(2-methoxyethoxymethoxy)biphenyl-4-carboxylate

[0360] 10 g (43.8 mmol) of 4′-hydroxybiphenyl-4-carboxylic acid methylester, 100 ml of THF and 150 ml of DMF are introduced in order and undera nitrogen stream into a 500 ml three-necked flask. 1.93 g (48.2 mmol)of NaH at 60% in oil are added in small portions and the mixture isstirred at room temperature for 15 hours. 5.75 ml of1-chloromethoxy-2-methoxyethane are added dropwise, and the mixture isstirred at room temperature for 30 minutes. The reaction medium ispoured over a 1N HCl solution and extracted with ethyl acetate. Theorganic phase is washed with water and dried over magnesium sulphate.After filtration and evaporation 12 g of4′-(2-methoxyethoxymethoxy)biphenyl-4-carboxylic acid methyl ester areobtained in the form of a beige powder after filtration and evaporation(yield=87%).

[0361] (b) 4′-(2-methoxyethoxymethoxy)biphenyl-4-carboxylic Acid

[0362] 10 g (31.6 mmol) of4′-(2-methoxyethoxymethoxy)biphenyl-4-carboxylic acid methyl ester, 100ml of methanol and 31 ml of a 10 M NaOH solution are introduced, inorder, into a 250 ml three-necked flask. The mixture is stirred at 80°C. for 30 minutes. After returning to room temperature, the reactionmedium is poured over water and acidified with a 1 N HCl solution. Theprecipitate is filtered off. It is taken up in heptane. After filteringand drying, 9 g of 4′-(2-methoxyethoxymethoxy)biphenyl-4-carboxylic acidare obtained in the form of a beige powder (yield=98%).

[0363] (c) 4′-(2-methoxyethoxymethoxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbiphenyl-4-carboxamide

[0364] In a manner similar to Example 12, by reacting 4 g (12.3 mmol) of5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dioneobtained in 1(f) with 3.58 g (12.3 mmol) of4′-(2-methoxyethoxymethoxy)biphenyl-4-carboxylic acid, 2.9 g (38%) of4′-(2-methoxyethoxymethoxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbiphenyl-4-carboxamideare obtained in the form of a white powder having a melting point of126-128° C. after purification by chromatography on a silica columneluted with a heptane and ethyl acetate (50/50) mixture, followed byrecrystallization from methanol.

[0365]¹H NMR (DMSO d6; 400 MHz): 2.93 (m, 3H); 3.15-3.22 (m, 4H);3.41-3.47 (m, 3H); 3.72 (m, 2H); 4.61-4.75 (m, 2H); 4.96 (dd, J=4.3 Hzand J=9.1 Hz, 1H); 5.29 (broad s, 2H); 7.11-7.68 (m, 16H); 12.10 (broads, 1H).

EXAMPLE 33

[0366]4′-hydroxy-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbiphenyl-4-carboxamide

[0367] 1.6 g of4′-(2-methoxyethoxymethoxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbiphenyl-4-carboxamide,100 ml of methanol and 1 ml of 98% sulphuric acid are introduced, inorder, into a 250 ml three-necked flask. The mixture is stirred at roomtemperature for 18 hours. The reaction medium is concentrated. It istaken up in ethyl acetate and it is washed twice with water. The organicphase is dried over magnesium sulphate. After filtration andevaporation, the product obtained is recrystallized from anacetone/dichloromethane mixture. After filtration and drying, 1.34 g(99%) of4′-hydroxy-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbiphenyl-4-carboxamideare obtained in the form of a white powder having a melting point of211-213° C.

[0368]¹H NMR (DMSO d6; 400 MHz): 2.93 (m, 3H); 3.18 (dd, J=9.6 Hz andJ=14.1 Hz, 1H); 3.43 (dd, J=4.3 Hz and J=14.1 Hz, 1H); 4.61-4.75 (m,2H); 4.96 (dd, J=4.3 Hz and J=9.6 Hz, 1H); 6.85-7.63 (m, 16H); 9.62(broad s, 1H); 12.10 (broad s, 1H).

EXAMPLE 34

[0369]1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-3-(4-hexyloxyphenyl)-1-methylurea

[0370] (a) tert-butyl (3-bromophenyl)carbamate

[0371] 667 g (3 mol) of di-tert-butyl dicarbonate are introduced into a10 litre round-bottomed flask. 4.5 litres of a 2 M sodium hydroxidesolution and 453 g (2.58 mol) of 3-bromoaniline are added undernitrogen. The mixture is heated under reflux for 4.5 hours. The reactionmedium is extracted with ethyl acetate, the organic phase is washed withwater and then evaporated under vacuum. The solid obtained is taken up,with stirring, in heptane. After filtration and drying, 609 g (86%) oftert-butyl (3-bromophenyl)carbamate are obtained in the form of a whitepowder.

[0372] (b) tert-butyl (3-bromophenyl)methylcarbamate

[0373] 9.33 g (0.22 mol) of NaH at 60% in oil and 250 ml of DMF areintroduced under nitrogen into a round-bottomed flask. 53 g (0.18 mol)of (3-bromophenyl)carbamic acid tert-butyl ester in solution in 150 mlof DMF are added dropwise. After 10 minutes, 14.5 ml (0.22 mmol) ofmethyl iodide are added dropwise. The mixture is stirred at roomtemperature for 30 minutes. After filtration of the NaI and evaporationof the DMF, the medium is solubilized in 350 ml of ethyl acetate andwashed with twice 300 ml of water. After drying over sodium sulphate andevaporation of the solvents, 55 g (98%) of tert-butyl(3-bromophenyl)methylcarbamate are obtained in the form of a yellowliquid.

[0374] (c) tert-butyl (4′-formylbiphenyl-3-yl)methylcarbamate

[0375] In a manner similar to Example 1(c), by reacting 55 g (0.19 mol)of tert-butyl (3-bromophenyl)methylcarbamate with 50.5 g (0.30 mol) of4-formylbenzeneboronic acid, 48 g (80%) of tert-butyl(4′-formylbiphenyl-3-yl)methylcarbamate are obtained after purificationby chromatography on a silica column eluted with a heptane and ethylacetate (90/10) mixture.

[0376] (d) tert-butyl[4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-yl]methylcarbamate

[0377] In a manner similar to Example 1(d), by reacting 40 g (0.128 mol)of tert-butyl (4′-formylbiphenyl-3-yl)methylcarbamate with 15 g (0.128mol) of 2,4-thiazolidinedione and 3.7 g (0.025 mol) of piperidiniumacetate and 0.4 l of toluene, 42.8 g (81.6%) of tert-butyl[4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-yl]methylcarbamateare obtained.

[0378] (e) tert-butyl [4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]methylcarbamate

[0379] 3.69 g (0.009 mol) of tert-butyl[4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-yl]methylcarbamate,6 ml of THF and 7.3 ml of pyridine are introduced, in order, into a 50ml three-necked round-bottomed flask. The mixture is placed undernitrogen and 10 ml of a freshly prepared 2 M LiBH₄ solution (0.02 mol)in THF are added dropwise. After stirring for 30 minutes at roomtemperature, the mixture is heated under reflux for 16 hours. Thereaction medium is poured over 32 ml of a 1 N HCl solution and the THFis evaporated under vacuum. The precipitate obtained is filtered. Afterdrying, the crude product (2.75 g) is chromatographed on 95 g of silicagel, eluting with a heptane/ethyl acetate=3/7 mixture. 2.45 g (66%) oftert-butyl[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]methylcarbamate areobtained.

[0380] (f) 5-(3′-methylaminobiphenyl-4-ylmethyl)thiazolidine-2,4-dione

[0381] 2.32 g (5.6 mmol) of[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]methylcarbamic acidtert-butyl ester, 40 ml of dichloromethane and 6.4 g (56 mmol) oftrichloroacetic acid are introduced into a 100 ml round-bottomed flask.After stirring for 24 h at room temperature, the reaction medium isconcentrated in a rotary evaporator and taken up in diisopropyl ether.After trituration and stirring, it is filtered, taken up in 50 ml ofwater and neutralized with 0.53 g (6.2 mmol) of sodium bicarbonate. Theprecipitate is filtered, washed with ethyl ether and dried under vacuum.1.43 g (81.7%) of5-(3′-methylaminobiphenyl-4-ylmethyl)thiazolidine-2,4-dione are obtainedin the form of a white powder.

[0382] (g)1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-3-(4-hexyloxyphenyl)-1-methylurea

[0383] 0.67 g (2.14 mmol) of5-(3′-methylaminobiphenyl-4-ylmethyl)thiazolidine-2,4-dione in 20 ml ofdichloromethane is introduced into a 50 ml round-bottomed flask. 1 g(4.3 mmol) of 1-hexyloxy-4-isocyanatobenzene is added and the mixture isheated under reflux for 16 hours. The reaction medium is poured at roomtemperature over a 1 N HCl solution and extracted with ethyl acetate.The organic phase is washed with water and dried over magnesiumsulphate. After evaporation of the solvents, the product obtained ispurified by chromatography on silica gel (eluent: heptane/ethylacetate=3/2). 0.78 g (68%) of1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-3-(4-hexyloxyphenyl)-1-methylureais obtained in the form of a white powder having a melting point of146-148° C.

[0384]¹H NMR (DMSO d6; 400 MHz): 0.81 (t, 3H); 1.29 (m, 4H); 1.39 (m,2H); 1.67 (m, 2H); 3.18 (dd, J=9.6 Hz and J=14.1 Hz, 1H); 3.31 (s, 3H);3.43 (dd, J=4.3 Hz and J=14.1 Hz, 1H); 3.90 (m, 2H); 4.96 (dd, J=4.3 Hzand J=9.6 Hz, 1H); 6.80 (m, 2H); 7.28-7.66 (m, 10H); 8.07 (s, 1H); 12.10(broad s, 1H).

EXAMPLE 35

[0385] Transactivation Test

[0386] The agonist activity towards the PPARγ receptors of the compoundsaccording to the invention may be evaluated by transactivation tests.

[0387] The capacity of the molecules to activate and/or inhibit thePPARγ receptors is evaluated from Hela cells stably transfected with thechimeric Gal-PPARγ receptor (LBD).

[0388] 96-well plates are inoculated at the rate of 10 000 cells/100μl/well in DMEM 10% SDL medium and then placed for 24 hours at 37° C.,7% CO₂.

[0389] To determine the PPARγ agonist activity, the cells are thentreated by addition of 5 μl/well of the molecules to be tested at thefinal concentration of 1 μM. Cells are also treated in parallel with areference agonist,(−)-3-{4-[2-(benzooxazol-2-ylmethylamino)ethoxy]phenyl}-2-ethoxypropionicacid, 1 μM.

[0390] After another incubation of 24 hours at 37° C., 7% CO₂, aluciferase assay is carried out with the aid of the “Steady-GloLuciferase Assay System” kit from Promega. The luminescence is countedon a Microbeta Trilux microplate reader (Wallac).

[0391] The agonist activity of the test product will be expressed as apercentage activation relative to the control agonist, the referenceagonist at 1 μM.

[0392] By applying this same protocol with the chimeric Gal-PPARαreceptor, it is possible to measure the agonist activity of thecompounds towards the PPARalpha receptors and thus to compare it withthat of the PPARγ receptor.

[0393] The AC50, expressed in nM, is determined as the concentrationwhich makes it possible to obtain 50% activation of the basal signalrelative to the reference agonist.

[0394] The results obtained for the compounds according to the inventionare grouped together in the following table: % Activation (at 1 microM)AC50 (in nM) PPARα PPARγ PPARα PPARγ Compound of 13.7 N.Y. N.T 55.5Example 2 Compound of 22.3 N.T. >50 000.0 13.1 Example 3 Compound of39.8 N.T. >50 000.0 24.2 Example 4 Compound of 26.6 N.T. >50 000.0 23.3Example 5 Compound of 7.9 N.T. <50 000.0 4.0 Example 6 Compound of 37.897.2 N.T. 63.8 Example 7 Compound of 33.6 97.2 N.T. 307.3 Example 8Compound of 4.3 105.9 N.T. 181.9 Example 9 Compound of 13.75 183.2 >50000.0 3.3 Example 10 Compound of 13.15 90.1 >50 000.0 15.1 Example 11Compound of 12.3 167.9 >50 000.0 3.2 Example 12 Compound of 13.4112.3 >50 000.0 36.7 Example 13 Compound of 19.1 76.7 N.T. 142.8 Example14 Compound of 28.8 101.6 >50 000.0 5.0 Example 15 Compound of 22.993.3 >50 000.0 0.55 Example 16 Compound of 15.1 96.1 >50 000.0 3.8Example 17 Compound of 37.3 90.7 >50 000.0 42.5 Example 18 Compound of100.2 102.1 >50 000.0 2.9 Example 19 Compound of 41.9 113.5 >50 000.07.7 Example 20 Compound of −4.2 104.2 N.T. 22 Example 21 Compound of−3.9 108.3 N.T. 4.2 Example 22 Compound of 11.9 90.0 N.T. 1.0 Example 23

[0395] These results show the transactivation activity of the compoundsaccording to the invention. These results show more particularly thespecificity of the activation of the compounds of the invention for thePPPR-γ subtype compared with the activation of the compounds for thePPAR-α subtype.

EXAMPLE 36

[0396] Binding Test

[0397] The affinity of the compounds of the invention for the humanPPARγ receptor was determined in a test of binding, by competition forthe attachment of a reference agonist, the following tritiated compound5-{4-[2-(methylpyridin-2-ylamino)ethoxy]benzyl}thiazolidine-2,4-dione.

[0398] The receptors are obtained by infecting SF9 insect cells with arecombinant bacculovirus. They exist in the form of hPPARγ/RXRαheterodimers. The presence of RXRα increases the solubility and thestability of the hPPARγ receptor and, consequently, its biologicalactivity, without as a result interfering in the determination of thebinding constants.

[0399] The technique of adsorption on hydroxyapatite gel was used toseparate the ligand bound to the receptor from the free ligand. Theresults are expressed as Kd value (nM) which represents the dissociationconstant at equilibrium obtained for each compound.

[0400] The results obtained for the compounds according to the inventionare grouped together in the following table: Binding to PPARγ Kd (in nM)Compound of Example 3 375.0 Compound of Example 4 250.0 Compound ofExample 5 500.0 Compound of Example 6 60.0 Compound of Example 10 60.0Compound of Example 11 375.0 Compound of Example 12 60.0 Compound ofExample 13 500.0 Compound of Example 15 60.0 Compound of Example 16 4.0Compound of Example 17 15.0 Compound of Example 19 8.0 Compound ofExample 20 9.5

[0401] These results show the very good affinity of the compoundsaccording to the present invention for the PPARγ receptor.

EXAMPLE 37

[0402] Various concrete formulations based on the compounds according tothe invention have been illustrated in this example.

[0403] A-Oral Route

[0404] (a) 0.2 g tablet Compound of Example 16 0.001 g Starch 0.114 gBicalcium phosphate 0.020 g Silica 0.020 g Lactose 0.030 g Talc 0.010 gMagnesium stearate 0.005 g (b) Oral suspension in 5 ml vials Compound ofExample 17 0.001 g Glycerine 0.500 g Sorbitol at 70% 0.500 g Sodiumsaccharinate 0.010 g Methyl para-hydroxybenzoate 0.040 g Flavouring qsPurified water qs 5 ml (c) 0.8 g tablet Compound of Example 19 0.500 gPregelatinized starch 0.100 g Microcrystalline cellulose 0.115 g Lactose0.075 g Magnesium stearate 0.010 g (d) Oral suspension in 10 ml vialsCompound of Example 20 0.200 g Glycerine 1.000 g Sorbitol at 70% 1.000 gSodium saccharinate 0.010 g Methyl para-hydroxybenzoate 0.080 gFlavouring qs Purified water qs 10 ml B- TOPICAL ROUTE (a) SalveCompound of Example 12 0.020 g Isopropyl myristate 81.700 g Fluid liquidparaffin 9.100 g Silica (“Aerosil 200” sold by DEGUSSA) 9.180 g (b)Salve Compound of Example 15 0.300 g Petroleum jelly qs 100 g (c)Nonionic water-in-oil cream Compound of Example 10 0.100 g Mixture ofemulsifying lanolin alcohols, 39.900 g waxes and oils (“anhydrouseucerin” sold by BDF) Methyl para-hydroxybenzoate 0.075 g Propylpara-hydroxybenzoate 0.075 g Sterile demineralized water qs 100 g (d)Lotion Compound of Example 19 0.100 g Polyethylene glycol (PEG 400)69.900 g Ethanol at 95% 30.000 g (e) Hydrophobic salve Compound ofExample 20 0.300 g Isopropyl myristate 36.400 g Silicon oil (“Rhodorsil47 V 300” sold 36.400 g by RHONE-POULENC) Beeswax 13.600 g Silicone oil(“Abil 300,000 cst” qs 100 g sold by GOLDSCHMIDT) (f) Nonionicoil-in-water cream Compound of Example 16 1.000 g Cetyl alcohol 4.000 gGlyceryl monostearate 2.500 g PEG 50 stearate 2.500 g Shea butter 9.200g Propylene glycol 2.000 g Methyl para-hydroxybenzoate 0.075 g Propylpara-hydroxybenzoate 0.075 g Sterile demineralized water qs 100 g

[0405] While the invention has been described in terms of variousspecific and preferred embodiments, the skilled artisan will appreciatethat various modifications, substitutions, omissions, and changes may bemade without departing from the spirit thereof. Accordingly, it isintended that the scope of the present invention be limited solely bythe scope of the following claims, including equivalents thereof.

What is claimed is:
 1. A compound having the following structuralformula (I):

in which R₁ is a radical of the following formulae (a) or (b):

wherein R₅ and R₆ are as defined below; R₂ and R₃, which may beidentical or different, are each a hydrogen atom, an alkyl radicalhaving from 1 to 6 carbon atoms, an aryl radical, a halogen atom, aradical —OR₇, a polyether radical, a nitro group or an amino group whichmay be optionally substituted with alkyl radicals having from 1 to 6carbon atoms, wherein R₇ is as defined below; X is one of the radicalshaving the following structures: —CH₂—N(R₈)—CO— —N(R₈)—CO—N(R₉)——N(R₈)—CO—CH₂— —N(R₈)—CH₂—CO— whether read from left to right or viseversa, wherein R₈ and R₉ are as defined below; R₄ is a phenyl, benzyl,phenethyl, thienyl, furyl or pyridyl radical, each of these radicalsbeing substituted with a group R₁₀, wherein R₁₀ is as defined below, apyrrolyl, pyrazinyl, naphthyl, biphenyl, indolyl, indenyl, benzothienyl,benzofuryl, benzothiazolyl or quinolyl radical, with the proviso thateach of these radicals may be mono- or disubstituted with a group R₁₁and/or R₁₂, wherein R₁₁ and R₁₂ are as defined below a radical—(CH₂)n—(CO)_(q)R₁₃, wherein n, q and R₁₃ are as defined below, anadamantyl, diphenylmethyl, diphenylethyl, diphenylpropyl, diphenylbutyl,cyclopropylmethyl, cyclopentylethyl, 2-benzimidazolyl-ethyl,cyclohexylmethyl, phenoxyphenyl, 9H-fluorenyl, benzyloxyphenyl,4-heptyloxyphenyl, or 4-(6-methyl-2-benzothiazolyl)phenyl radical, or aradical —(CH₂)n—O—R₁₃, wherein n and R₁₃ are as defined below; R₅ is ahydroxyl group or an alkoxy radical having from 1 to 9 carbon atoms; R₆is an alkyl radical having from 1 to 6 carbon atoms, a radical OR₁₄ or aradical SR₁₄, wherein R₁₄ is as defined below; R₇ is a hydrogen atom, analkyl radical having from 1 to 6 carbon atoms, an aryl radical or anaralkyl radical; R₈ is a hydrogen atom or an alkyl radical having from 1to 6 carbon atoms; R₉ is a hydrogen atom or an alkyl radical having from1 to 6 carbon atoms; R₁₀ is a radical —S(O)_(m)R₁₅, a radical—(CH₂)p—COR₁₆, or a radical —O—R₁₇, wherein m, p, R₁₅, R₁₆ and R₁₇ areas defined below; R₁₁, and R₁₂ are each a halogen atom, a radical CF₃,an alkyl radical having from 1 to 12 carbon atoms, an alkoxy radicalhaving from 1 to 9 carbon atoms, a polyether radical, a nitro functionalgroup, a hydroxyl group optionally protected by an acetyl or benzoylgroup, an amino functional group optionally substituted with at leastone alkyl radical having from 1 to 12 carbon atoms or with a radical—CONH—R₂₄, or protected by an acetyl or benzoyl group, a radical—S(O)_(m)R₁₅, a radical (CH₂)p—COR₁₆ or a radical —OR₁₇, wherein m, p,R₁₅, R₁₆, R₁₇ and R₂₄ are as defined below; n is a number ranging from 1to 9; q is 0 or 1; R₁₃ is a radical —OR₁₈, a radical —N(R₁₉)(R₂₀), anaryl radical, an aralkyl radical or a heteroaryl radical, wherein R₁₈,R₁₉ and R₂₀ are as defined below; m is 0, 1 or 2; p is 0, 1 or 2, R₁₄ isan alkyl radical having from 1 to 12 carbon atoms, a radical CF₃, anaryl radical or an aralkyl radical; R₁₅ is an alkyl radical having from1 to 12 carbon atoms, an aryl radical or an aralkyl radical; R₁₆ is analkyl radical having from 1 to 12 carbon atoms, a radical —OR₂₁, aradical —N(R₂₂)(R₂₃), an aryl radical or an aralkyl radical, whereinR₂₁, R₂₂ and R₂₃ are as defined below; R₁₇ is an aryl radical or anaralkyl radical; R₁₈ is a hydrogen atom or an alkyl radical having from1 to 12 carbon atoms; R₁₉ and R₂₀, which may be identical or different,are each a hydrogen atom, an alkyl radical having from 1 to 12 carbonatoms, or may together form a heterocycle; R₂₁ is a hydrogen atom or analkyl radical having from 1 to 12 carbon atoms; R₂₂ and R₂₃, which maybe identical or different, are each a hydrogen atom, an alkyl radicalhaving from 1 to 12 carbon atoms, or may together form a heterocycle;R₂₄ is a phenyl, diphenylmethyl, diphenylpropyl, diphenylbutyl,biphenylyl, phenoxyphenyl, 9H-fluorenyl, 4-benzyloxyphenyl,4-heptyloxyphenyl, or 4-(6-methyl-2-benzothiazolyl)phenyl radical; or asalt of a compound of formula (I) when R₁ contains a carboxylic acidfunctional group and the optical and geometric isomers of said compoundsof formula (I).
 2. A compound as defined by claim 1, comprising a saltof an alkali or alkaline earth metal, a zinc salt, or a salt of anorganic amine.
 3. A compound as defined by claim 1, comprising at leastone alkyl radical having from 1 to 6 carbon atoms selected from amongthe methyl, ethyl, isopropyl, butyl, tert-butyl and hexyl radicals.
 4. Acompound as defined by claim 1, comprising at least one alkyl radicalhaving from 1 to 12 carbon atoms selected from among the methyl, ethyl,isopropyl, butyl, tert-butyl, hexyl, octyl, decyl and dodecyl radicals.5. A compound as defined by claim 1, comprising at least one polyetherradical having from 1 to 6 carbon atoms interrupted by at least oneoxygen atom.
 6. A compound as defined by claim 1, comprising at leastone fluorine, chlorine and/or bromine atom.
 7. A compound as defined byclaim 1, comprising at least one alkoxy radical having from 1 to 9carbon atoms selected from among the methoxy, ethoxy, isopropyloxy,tert-butoxy and hexyloxy radicals.
 8. A compound as defined by claim 1,comprising at least one aryl radical selected from among a phenyl ornaphthyl radical which may be mono- or disubstituted with a halogenatom, a radical CF₃, an alkyl radical having from 1 to 12 carbon atoms,an alkoxy radical having from 1 to 6 carbon atoms, a nitro functionalgroup, a polyether radical, a hydroxyl group optionally protected by anacetyl or benzoyl group or an amino functional group optionallyprotected by an acetyl or benzoyl group or optionally substituted withat least one alkyl radical having from 1 to 12 carbon atoms.
 9. Acompound as defined by claim 1, comprising at least one aralkyl radicalselected from among a benzyl or phenethyl radical which may be mono- ordisubstituted with a halogen atom, a radical CF₃, an alkyl radicalhaving from 1 to 12 carbon atoms, an alkoxy radical having from 1 to 6carbon atoms, a nitro functional group, a polyether radical, a hydroxylgroup optionally protected by an acetyl or benzoyl group or an aminofunctional group optionally protected by an acetyl or benzoyl group oroptionally substituted with at least one alkyl radical having from 1 to12 carbon atoms.
 10. A compound as defined by claim 1, comprising atleast one heteroaryl radical selected from among a pyridyl, furyl,thienyl and/or isoxazolyl radical, optionally substituted with at leastone halogen atom, an alkyl radical having from 1 to 12 carbon atoms, analkoxy radical having from 1 to 6 carbon atoms, a nitro functionalgroup, a polyether radical, a hydroxyl radical optionally protected byan acetyl or benzoyl group or an amino functional group optionallyprotected by an acetyl or benzoyl group or optionally substituted withat least one alkyl radical having from 1 to 12 carbon atoms.
 11. Acompound as defined by claim 1, comprising at least one heterocycleselected from among a piperidino, morpholino, pyrrolidino or piperazinoradical optionally substituted with an alkyl radical having from 1 to 12carbon atoms.
 12. A compound as defined by claim 1, comprising: 1-methyl7-{[4′-(2,4-dioxothiazolidin-5-ylmethyl)-biphenyl-3-ylmethyl]methylcarbamoyl}heptanoate;2-methyl9-{[4′-(2,4-dioxothiazolidin-5-ylmethyl)-biphenyl-3-ylmethyl]methylcarbamoyl}nonanoate;3-methylN-[4′-(2,4-dioxothiazolidin-5-ylmethyl)-biphenyl-3-ylmethyl]-N-methylterephthalamate;4-3-cyclopentyl-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylpropionamide;5-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-1-carboxamide;6-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;7-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-2-phenoxyacetamide;8-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-1-methyl-1H-pyrrole-2-carboxamide;9-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyladamantane-1-carboxamide;10-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbiphenyl-4-carboxamide;11-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbenzo[b]thiophene-2-carboxamide;12-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-6-oxo-6-phenylhexanamide;13-4-dimethylamino-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-1-carboxamide;14-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-4-methanesulphonyl-N-methylbenzamide;15-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4-(1-phenylmethanoyl)benzamide;16-6-(2-methoxyethoxymethoxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;17-6-hydroxy-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)-biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;18-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4-methylsulphanylbenzamide;19-(S)-3-(3′-{[(1-biphenyl-4-ylmethanoyl)methyl-amino]methyl}biphenyl-4-yl)-2-ethoxypropionicacid;20-(S)-2-ethoxy-3-(3′-{[methyl-(6-oxo-6-phenylhexanoyl)amino]methyl}biphenyl-4-yl)propionicacid;21-1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-1-methyl-3-naphthalen-2-ylurea;22-3-(4-dimethylaminophenyl)-1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-1-methylurea;23-(S)-2-ethoxy-3-{3′-[({1-[6-(2-methoxyethoxy-methoxy)naphthalen-2-yl]methanoyl}methylamino)methyl]-biphenyl-4-yl}propionicacid;24-6-(methoxymethoxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;25-6-(methoxycarbonyl)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;26-6-(propyloxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;27-6-(hexyloxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;28-6-(nonyloxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;29-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4′-propylbiphenyl-2-carboxamide;30-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4-phenoxybenzamide;31-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-7-oxo-7-phenylheptanamide;32-(6-{[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamoyl}naphthalen-2-yloxy)aceticacid;33-(6-{[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamoyl}naphthalen-2-yloxy)aceticacid methyl ester;34-6-methoxy-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;35-6-acetoxy-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;36-6-amino-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;37-6-acetylamino-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;38-1-hydroxy-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;39-1-methoxy-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;40-6-bromo-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;41-6-carboxyl-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;42-6-carboxyl-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamidemethyl ester;43-6-(3-phenylureido)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;44-3-hydroxy-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;45-3-methoxy-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide;46-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4′-hydroxybiphenyl-4-carboxamide;47-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4′-methoxybiphenyl-4-carboxamide;48-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4′-propyloxybiphenyl-4-carboxamide;49-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4′-hexyloxybiphenyl-4-carboxamide;50-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4′-acetoxybiphenyl-4-carboxamide;51-(4′-{[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamoyl}biphenyl-4-yloxy)aceticacid;52-(4′-{[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamoyl}biphenyl-4-yloxy)aceticacid methyl ester;53-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4′-methoxymethoxybiphenyl-4-carboxamide;54-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4′-nonyloxybiphenyl-4-carboxamide;55-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-4′-(2-methoxyethoxy)biphenyl-4-carboxamide;56-3-biphenyl-4-yl-1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-1-methylurea;57-1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-3-(9H-fluoren-2-yl)-1-methylurea;58-1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-3-(9H-fluoren-9-yl)-1-methylurea;59-3-benzhydryl-1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-1-methylurea;60-1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-1-methyl-3-(3-phenoxyphenyl)urea;61-1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-3-(4-heptyloxyphenyl)-1-methylurea;62-3-(4-benzyloxyphenyl)-1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-1-methylurea;63-1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-1-methyl-3-[4-(6-methylbenzothiazol-2-yl)phenyl]urea;64-4′-(2-methoxyethoxymethoxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbiphenyl-4-carboxamide;65-4′-hydroxy-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbiphenyl-4-carboxamide;66-1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-3-(4-hexyloxyphenyl)-1-methylurea;or mixture thereof.
 13. A compound as defined by claim 1, wherein R₁ isthe radical of formula (a) or the radical of formula (b) in which R₅ isa hydroxyl group and R₆ is the radical OR₁₄ and/or X is a radical havingthe structure —CH₂—N(R₈)—CO— or —N(R₈)—CO—N(R₉)— read from left to rightor vise versa.
 14. A regime or regimen for regulating and/or restoringskin lipid metabolism, comprising administering to an individual subjectin need of such treatment, an effective amount of a compound as definedin claim
 1. 15. A regime or regimen for the treatment: of dermatologicalconditions linked to a keratinization disorder related to celldifferentiation and proliferation; of ichtyosis, ichtyosiform states,Darrier's disease, keratosis palmaris et plantaris, leukoplasia andleukoplasiform states, cutaneous or mucosal (buccal) lichen; ofdermatological afflictions with an inflammatory immunoallergiccomponent, with or without cell proliferation disorder; of benign ormalignant dermal or epidermal proliferations, of viral or nonviralorigin; of proliferations which may be induced by ultraviolet radiation;of precancerous skin lesions; of immune dermatoses; of bullous immunediseases; of collagen diseases; of dermatological or general afflictionshaving an immunological component; of skin disorders due to exposure toUV radiation, skin aging, photoinduced or chronological or actinicpigmentations and keratoses; of pathologies associated withchronological or actinic aging; of sebaceous function disorders; ofcicatrization disorders or of stretch marks; or of pigmentationdisorders, comprising administering to an individual subject in need ofsuch treatment, an effective amount of a compound as defined in claim 1.16. A regime or regimen for the treatment of a dermatological conditionlinked to a keratinization disorder, acne vulgaris, comedo-type acne,polymorphic acne, acne rosacea, nodulocystic acne, acne conglobata,senile acne, secondary acne, solar acne, acne medicamentosa oroccupational acne, comprising administering to an individual subject inneed of such treatment, an effective amount of a compound as defined inclaim
 1. 17. A regime or regimen for the treatment of cutaneous, mucosalor ungual psoriasis, psoriatic rheumatism or cutaneous atopy, eczema,respiratory atopy or gingival hypertropy, comprising administering to anindividual subject in need of such treatment, an effective amount of acompound as defined in claim
 1. 18. A regime or regimen for thetreatment of verruca vulgaris, verruca plana, epidermodysplasiaverruciformis, oral or florid papillomatoses, or T lymphoma, comprisingadministering to an individual subject in need of such treatment, aneffective amount of a compound as defined in claim
 1. 19. A regime orregimen for the treatment of baso- or spinocellular epitheliomas,comprising administering to an individual subject in need of suchtreatment, an effective amount of a compound as defined in claim
 1. 20.A regime or regimen for the treatment of keratoacanthomas, comprisingadministering to an individual subject in need of such treatment, aneffective amount of a compound as defined in claim
 1. 21. A regime orregimen for the treatment of lupus erythematosus, comprisingadministering to an individual subject in need of such treatment, aneffective amount of a compound as defined in claim
 1. 22. A regime orregimen for the treatment of scleroderma, comprising administering to anindividual subject in need of such treatment, an effective amount of acompound as defined in claim
 1. 23. A regime or regimen for thetreatment of xerosis, comprising administering to an individual subjectin need of such treatment, an effective amount of a compound as definedin claim
 1. 24. A regime or regimen for the treatment of acnehyperseborrhoea or simple seborrhoea, comprising administering to anindividual subject in need of such treatment, an effective amount of acompound as defined in claim
 1. 25. A regime or regimen for thetreatment hyperpigmentation, melasma, hypopigmentation or vitiligo,comprising administering to an individual subject in need of suchtreatment, an effective amount of a compound as defined in claim
 1. 26.A pharmaceutical composition comprising at least one compound as definedin claim 1, formulated into a physiologically acceptable carriertherefor.
 27. A composition as defined by claim 25, comprising from0.001% to 10% by weight relative to the total weight of the compositionof said at least one compound.
 28. A composition according to claim 26,comprising from 0.01% to 1% by weight relative to the total weight ofthe composition of said at least one compound.
 29. A cosmeticcomposition comprising at least one compound as defined in claim 1,formulated into a cosmetically acceptable carrier therefor.
 30. Thecomposition as defined by claim 29, comprising from 0.001% to 3% byweight relative to the total weight of the composition of said at leastone compound.
 31. A regime or regimen for preventing and/or treating thesigns of aging and/or dry skin, comprising administering to anindividual subject in need of such treatment, an effective amount of acompound as defined in claim
 1. 32. A regime or regimen for body or hairhygiene, comprising topically applying thereon an effective amount ofthe cosmetic composition as defined by claim 29.